PBPrimate BiologyPBPrimate Biol.2363-4715Copernicus GmbHGöttingen, Germany10.5194/pb-2-25-2015Early development of the nervous system of the eutherian Tupaia belangeriKnabeW.w.knabe@uni-muenster.deWashausenS.https://orcid.org/0000-0003-1482-2761Prosektur Anatomie, Westfälische Wilhelms-Universität, 48149 Münster, GermanyW. Knabe (w.knabe@uni-muenster.de)16June201521255616April201511May201512May2015This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/This article is available from https://pb.copernicus.org/articles/2/25/2015/pb-2-25-2015.htmlThe full text article is available as a PDF file from https://pb.copernicus.org/articles/2/25/2015/pb-2-25-2015.pdf
The longstanding debate on the taxonomic status of Tupaia belangeri (Tupaiidae, Scandentia,
Mammalia) has persisted in times of molecular biology and genetics. But way
beyond that Tupaia belangeri has turned out to be a valuable and widely accepted animal
model for studies in neurobiology, stress research, and virology, among
other topics. It is thus a privilege to have the opportunity to provide an
overview on selected aspects of neural development and neuroanatomy in
Tupaia belangeri on the occasion of this special issue dedicated to Hans-Jürg Kuhn.
Firstly, emphasis will be given to the optic system. We report rather
“unconventional” findings on the morphogenesis of photoreceptor cells, and
on the presence of capillary-contacting neurons in the tree shrew retina.
Thereafter, network formation among directionally selective retinal neurons
and optic chiasm development are discussed. We then address the main and
accessory olfactory systems, the terminal nerve, the pituitary gland, and the
cerebellum of Tupaia belangeri. Finally, we demonstrate how innovative 3-D reconstruction
techniques helped to decipher and interpret so-far-undescribed, strictly
spatiotemporally regulated waves of apoptosis and proliferation which pass
through the early developing forebrain and eyes, midbrain and hindbrain, and
through the panplacodal primordium which gives rise to all
ectodermal placodes. Based on examples, this paper additionally wants to
show how findings gained from the reported projects have influenced current
neuroembryological and, at least partly, medical research.
Introduction
Deciphering structure–function relationships was and still is a central
issue of anatomical research. In the field of modern embryology tremendous
efforts have been made to decode the cellular and molecular mechanisms
underlying key processes in the development of vertebrates. Using
ever-more-sophisticated methods, the preponderant implementation of this type of
research has brought about a plethora of fascinating insights. However, in a
countermove, multi-species analyses were abandoned in favor of studies with
just a few thoroughly examined organisms for reasons of content and, of course, also for economic reasons. This communication provides both
a brief description of the neurodevelopmental and neuroanatomical projects
which have been carried out by the groups of Hans-Jürg Kuhn and his
former students using Tupaia belangeri (Tupaiidae, Scandentia, Euarchontoglires, Eutheria,
Theria, Mammalia) as a model system, and an overview on how findings gained
from these projects have influenced current neuroembryological and medical
research.
Hans-Jürg Kuhn, in whose honor this special issue of Primate Biology is published, has
authored, supervised, and inspired basic embryological writings to
characterize “his” Tupaia model. On the other hand, Kuhn has provided
ideally and materially a long-term basis for future embryological research
projects, mainly by building a comprehensive collection of histological
series made from precisely staged paraffin- or resin-embedded embryos of
Tupaia belangeri. This collection is managed by the Senckenberg Research Institute
Frankfurt/Main, but housed in the Prosektur Anatomie of the Westfälische
Wilhelms-Universität Münster, where it is of benefit for research
projects of the group of Wolfgang Knabe which evolved from the former
department of Morphologie (Georg-August-Universität, Göttingen) led by Hans-Jürg
Kuhn.
At the beginning of our Tupaia project, comparative anatomical studies were
performed worldwide and in large numbers. Consequently, the phylogenetic
position of Tupaia belangeri was under discussion in Göttingen and elsewhere – and still
remains a matter of debate. Thus, after inclusion of molecular and genetic
analyses the exact degree of relationship among the orders Primates,
Dermoptera, and Scandentia within the superordinal group Euarchonta is still
unclear (Janečka et al., 2007; Nie et al., 2008), and examination of the
mitochondrial DNA even suggests a closer relationship between Scandentia and
Lagomorpha (Schmitz et al., 2000; Arnason et al., 2002), which, in combination
with rodents, have a sister-group relationship to Euarchonta.
Given the pragmatic value and the “transience” of biological
classifications, Kuhn recognized Tupaia belangeri standing “at the roots of Primates”. He
accepted the preliminary taxonomic status of tree shrews as a separate order
(Scandentia) and, already in Frankfurt, started to collect as many embryos
and nest young Tupaia belangeri as possible (Kuhn and Starck, 1966). After the optimization
of the breeding conditions for Tupaia belangeri in captivity (Schwaier, 1973, 1974), an
extensive investigation on the implantation, early placentation, and the
chronology of embryogenesis in Tupaia belangeri was published by Kuhn and Schwaier (1973)
using embryos from 10 different stages of development, which came from the
anatomical institute (Kuhn and Starck, 1966) and, mainly, from the former
Battelle Institute in Frankfurt (Fig. 1). However, entirely in line with the
already implied unwillingness to enter the arena of overhasty conclusions,
Kuhn and Schwaier (1973) stated that “more information must be collected
from nonspecialized mammals, the so-called Insectivora, Strepsirhini, and
others, before all these characteristics and the pattern of reproductive
biology of Tupaia can be included in the discussion of the systematic
position of the Tupaiidae. It is most important that exactly dated embryos
from animals bred under controlled conditions become available for future
studies”.
Both objectives were successfully fulfilled in Göttingen, where Kuhn managed
to establish a close, long-term cooperation between the anatomical institute
and the newly founded German Primate Center. During this period, basic
embryological data were predominantly published in the framework of doctoral
theses, and they covered five main topics:
the reproductive system (ovary: Kriesell, 1977; fallopian tube:
Köpsel, 1988; fertilization and cleavage: Herrmann, 1982; postpartum
erythrophagocytosis, iron storage, and iron secretion in the endometrium:
Zeller and Kuhn, 1994),
the cardiovascular system (venous system of the liver: Liebherr, 1983;
heart and epicardium: Kuhn and Liebherr, 1987, 1988; Schönemann, 1990;
Otte, 1991; sinus venosus: Maas, 1992; anterior cardinal vein and its
tributaries: Steinecker, 1989; arteries of the visceral arches: E. Dawid, 1989;
posterior cardinal vein: Klammler, 1990; arteries of the upper extremity:
Matsumoto et al., 1994; arteries of the lower extremity: Funke, 1995; Funke
and Kuhn, 1998),
the skull (dentition: Jerxsen, 1982; cranium: Zeller, 1983; primary
lateral wall of the skull: Bischoff, 1989),
the postcranial skeleton (Schumann, 1984; shoulder girdle: Eickhoff, 1989;
chorda dorsalis: B. Dawid, 1989; skeleton of the foot: Ernstberger, 1994, with U.
Zeller),
the nervous system (ontogenesis of the neocortex: Rehkämper, 1977;
pituitary gland: Blanck, 1983; retina: Kühne, 1983; Knabe, 1995).
In the mid-1990s, the embryological research focus of our
department increasingly shifted to the development of the nervous system of
Tupaia belangeri, and here specifically to the development of the visual system. There are
numerous anatomical features which make Tupaia belangeri highly suitable for studies on the
visual system (e.g., Zilles, 1978). Consequently, around 200 scientific
contributions on this subject have been published since 1966, dealing with
structure–function relationships of the visual cortex, superior colliculi,
lateral geniculate nuclei, pulvinar, optic tract, optic chiasm,
suprachiasmatic nucleus, accessory optic system, retina, dioptric apparatus,
and sclera.
Visual system“Lens mitochondria” in the cone inner segments
In contrast to many other mammals, the entire retina of Tupaia belangeri mainly contains
cones, whereas the number of rods amounts to only around 4 % on average
(Samorajski et al., 1966; Kühne, 1983; Immel and Fisher, 1985; Foelix et
al., 1987). Different from photoreceptor cells in mice and men, the nuclei of
these cones are not stacked upon one another, but clearly arranged in only
one row. Consequently, both the development of cones and rods (Knabe, 1995;
Knabe and Kuhn, 1996a, b, 1997, 1998a; Knabe et al., 1997) and the
establishment of the associated neural networks can be studied under
particularly favorable conditions (Müller and Peichl, 1991a, b; Engelmann
and Peichl, 1996; Sandmann et al., 1997; Knabe et al., 2007). On the other
hand, the tree shrew retina is consulted in clinical contexts due to its
extensive structural similarity to the primate retina, e.g., for
documentation of retinal thinnings following induced high myopia via in vivo
optical coherence tomography (Abbott et al., 2009, 2011).
Retinal cones of Tupaia belangeri demonstrate a further amazing structural feature. In their
inner segments – which, in the optical path, are situated immediately before
the light-perceiving cone outer segments – reside extraordinarily large
mitochondria with “unique patterns of concentric cristae arranged in highly
ordered whorls of lamellar configurations” (Samorajski et al., 1966;
Dieterich, 1968, 1969; Kühne, 1983; Foelix et al., 1987). According to
Foelix et al. (1987) these large mitochondria are formed by fusion of many
smaller ones.
Building on this state of the art, we have extensively investigated the
morphogenesis of megamitochondria in the retinal cones of Tupaia belangeri using 3-D
reconstruction techniques (Knabe, 1995; Knabe and Kuhn, 1996a). It turned out
that initially small, structurally unspecialized, and randomly distributed
mitochondria migrate into the developing inner segment, thereby exhibiting a
basal-to-apical size gradient which later is overlaid by a radial size
gradient. Furthermore, all megamitochondria are constructed according to a
basic building plan (Fig. 2a, b). They demonstrate a voluminous body
situated in the center of the inner segment. From these bodies protrude
long-drawn-out processes which run underneath the cell membrane and
apparently give off small mitochondria. In the absence of clear proof of
mitochondrial fusion, differential growth processes of individual
mitochondria should contribute to the morphogenesis of these
megamitochondria.
In the cone inner segments of Tupaia belangeri, long-drawn-out processes of megamitochondria
and their presumed small derivatives are particularly suited to serve
metabolic functions: first, due to their surface-to-volume ratio and,
second, due to their proximity to the cell membrane. However, for these same
reasons, an exclusive metabolic function of the voluminous, centrally
located bodies of these megamitochondria seemed unlikely. Instead, we felt
reminded of the “oil droplets” or “ellipsosomes” which, albeit of
unknown origin, are situated in identical positions in the cone inner
segments of teleosts, amphibians, reptiles, birds, and aplacental mammals (for
a review, see Knabe and Kuhn, 1996a). Resembling mitochondria, ellipsosomes
are ensheathed by a double membrane and may enclose rather diffuse
membranous structures (Berger, 1966; Ishikawa and Yamada, 1969; Kunz and
Regan, 1973; Kunz and Wise, 1978; for a review, see MacNichol Jr. et al., 1978). In
contrast, classical oil droplets are bounded by a single membrane,
demonstrate a completely homogeneous inner structure, and contain high
quantities of carotenoids (Ishikawa and Yamada, 1969; Hailman, 1976; Borwein,
1981). A clear dividing line between ellipsosomes and oil droplets does not
exist. However, it is widely accepted that usually colored oil droplets have
a high index of refraction, may direct light towards the outer segment,
and/or may filter out at least some wavelengths of the spectrum (Wolbarsht,
1976). In the light of these earlier results, our findings in Tupaia belangeri favor the
hypothesis that huge specialized organelles with accessory optical functions
have evolved from inner segment mitochondria in representatives from all
vertebrate classes, thereby exhibiting a variety of different structural
patterns ranging from “true” megamitochondria to highly modified oil
droplets (Knabe and Kuhn, 1996a).
In the cone inner segments of Tupaia belangeri the cristae of megamitochondria are organized
in the form of multilamellar wavelike crista-matrix systems (Fig. 2c) which
are longitudinally oriented towards the outer segment and which, even
between different individuals, demonstrate identical “frequencies”,
“wavelengths”, and “amplitudes” (Knabe, 1995; Knabe et al., 1997). In view
of this high degree of order, we decided to determine the refractive index
of isolated cone inner segments in cooperation with Sergej Skatchkov
(Laboratory of Neurobiology, University of Puerto Rico, San Juan, Puerto
Rico). It turned out that cone inner segments of Tupaia belangeri have higher refractive
indices than the cone inner segments of all other mammals investigated so
far (XA= 1.405), which nicely fits our postulate that huge “lens
mitochondria” may execute accessory optical functions (Knabe et al., 1997).
Precise knowledge of the refractive indices and of the geometry of
photoreceptor cells are required to further analyze the question how
exactly waveguide theories can be applied to photoreceptor cells (McIntyre
and Pask, 2013).
Reported characteristics of the retinal cones of Tupaia belangeri were quickly integrated in
the canon of retinological knowledge (Ahnelt and Kolb, 2000) and have
inspired quite numerous follow-up studies. It turned out that, contrary to
some expectations, the structural composition of the inner segment
mitochondria found in Tupaia belangeri is by no means the complete exception compared with
other mammals. Instead, megamitochondria with presumed accessory optical
functions were also discovered in the cone inner segments of several species
belonging to the genus Sorex (Insectivora, Soricidae). As is also the case
in Tupaiabelangeri, these megamitochondria (1) are situated in apical and central
positions of the inner segment, whereas additional small mitochondria reside
in its basal and peripheral parts; (2) possess an electron-dense matrix and
a complex system of cristae; and (3) demonstrate cristae displaying a
“continuous array from one large mitochondrion to several neighboring ones”
(Lluch et al., 2003, 2009). An equivalent to megamitochondria
also appears to exist in nocturnal Microcebus murinus (gray mouse lemur), which are the most
ancestral living primates. Dkhissi-Benyahya et al. (2001) argue that “for
the nocturnal mouse lemur, a gain in the sensitivity of cones could be
useful during periods of dawn and dusk when light levels are in the low
photopic range”.
The presence of megamitochondria in photoreceptor cells is not restricted to
mammals. Instead, megamitochondria also have been found in zebrafish, namely
in the inner segments of cones as well as rods (Kim et al., 2005). Going
beyond this initial characterization, Tarboush et al. (2012, 2014) have
focused on the development of megamitochondria in zebrafish photoreceptor
cells. Furthermore, these authors have assigned individual characteristics
of the inner segment mitochondria to each of the four different types of
cones as well as to rods. So far, similar efforts have not been successful in
Tupaia belangeri, although two types of cones have been characterized spectroscopically (Petry
and Hárosi, 1990) and immunocytochemically (Müller and Peichl, 1989).
Staining with toluidine blue even revealed three subpopulations of cones,
one of which is, however, unevenly distributed and, most probably,
pathologically altered (Müller and Peichl, 1989). Using electron
microscopy, Foelix et al. (1987) observed different electron densities in
the mitochondrial matrix of cones which, however, were randomly distributed.
With regard to “accessory” functions of megamitochondria in the inner
segments of zebrafish photoreceptor cells, Tarboush et al. (2014) primarily
suggest mechanisms of protection against apoptotic processes, mainly due to
the presence of crocetin, which reduces oxidative damage. Nevertheless, the
authors think it possible that highly refractive photoreceptor cells of
zebrafish act as light-funnelling devices, and they support our hypothesis that
especially the small mitochondria underneath the cell membrane drive the
energy metabolism (Tarboush et al., 2014).
In another teleost (Fundulus heteroclitus, killifish),
the inner segments of photoreceptor cells
do not contain megamitochondria in the proper sense, but instead a “variety
of ellipsosome-like bodies” (Flamarique and Hárosi, 2000). Based on
structural criteria, their descent from mitochondria is highly probable,
whereas presumed accessory optical functions are currently a matter of
speculation. According to Flamarique and Hárosi (2000), three different
types of specialized organelles (electron-dense bodies, ellipsosomes, and
pseudoellipsosomes with low optical density) are present in distal parts of
the inner segments of long/middle-, long/long-wavelength double cones, or in
single short-wavelength cones, respectively. Furthermore, these authors
provide evidence for the first time that different types of ellipsosomes
exist in photoreceptor cells taken from different parts of the retina.
“Large globules of mitochondrial origin” (ellipsosomes) with presumed
accessory optical functions also have been observed in the Southern
Hemisphere lamprey Geotria australis (Collin et al., 2003). This finding is particularly
revealing from a phylogenetic perspective, since lampreys and hagfishes
represent “the sole survivors of the very early agnathan (jawless) stage in
vertebrate evolution” (Hardisty, 1982). Interestingly, in Geotria australis, ellipsosomes
were exclusively found in medium-wavelength-sensitive cones of nocturnally
active upstream migrants, but not in downstream migrants (Collin et al.
2003). Hence, ellipsosomes replace the yellow, short wavelength absorbing
pigment present in downstream migrants and may help to trap photons.
Different from Geotria australis, not two types of cones but a single class of rod-like
photoreceptors with cone-like features was documented in the Southern
Hemisphere lamprey Mordacia mordax Richardson (Collin and Potter, 2000). Reminiscent of our
findings in Tupaia belangeri (Knabe and Kuhn, 1996a), these rods contain “a large
mitochondrial ellipsosome” on top of the inner segment mitochondria which
are roughly lined up along a basal-to-apical size gradient. The ellipsosomes
are dark without cristae, thus resembling the ellipsosomes of teleosts
(Collin and Potter, 2000). Finally, oil droplets but not ellipsosomes are
present in the cone inner segments of diurnal geckos, again on top of
mitochondria arranged along a basal-to-apical size gradient (Röll, 2000).
As a prerequisite for designing experiments which clarify how exactly
megamitochondria of the “Tupaia-type” influence the incoming light, the
physical properties of their crista architecture need to be characterized in
depth. Consequently, using the example of Tupaia belangeri, Almsherqi et al. (2012) dared to
have a “look through `lens' cubic mitochondria”. The 3-D simulation data
provided by them demonstrate that megamitochondria which contain multi-layer
cubic membrane structures may act as multifocal lenses, angle-independent
interference filters to block UV-light, and/or waveguide photonic crystals.
For a broader review on the properties of nanoperiodic cubic membranes see
Almsherqi et al. (2009).
An understanding of how multi-layer cubic membrane structures contribute to
the optic properties of megamitochondria will also help to characterize the
optical properties of less spectacular inner segments exhibiting neither
megamitochondria nor size gradients. In the simplest case, varying the
number of mitochondria in different photoreceptor cell types and/or in
different retinal positions may be sufficient to adjust the guidance of
light to particular requirements. In line with this hypothesis, peripheral
cones in Macaca arctoides contain excess mitochondria which possibly “enhance their
light-gathering properties”. Furthermore, the number of mitochondria is 10
times higher in cones compared to rods (Hoang et al., 2002).
Addressing the optical properties of photoreceptor cells which, by geometry
of the outer segment alone, “compensate for self-screening of the visual
pigments” and/or for a “signal-to-noise ratio decline along the
longitudinal dimension” (Hárosi and Novales Flamarique, 2012) will
remain a fascinating research objective. Introducing megamitochondria into
this field as a new mosaic piece has inspired the search for other
organelles which are placed in the optic pathway and which may have an
influence on the incoming light. Thus, it recently became clear that the rod
nuclei of nocturnal animals – unlike the “conventional” rod nuclei of
diurnal species – demonstrate a centrally located condensation of
heterochromatin. Due to the resulting increase of the refractive index, such
“inverted” rod nuclei may in fact “act as collecting lenses” (Solovei et
al., 2009). In this regard, exciting observations also have been published by
Joffe et al. (2014), who are interested in how diurnality has developed in
Primates. Based on the analysis of proteins responsible for the
marginalization of heterochromatin in rod nuclei, it turned out that primate
ancestors were nocturnal and that “transition to diurnality occurred
independently in several primate and related groups” including Tupaia. From
the authors' point of view, the “hemispherical lens formed by
a giant mitochondrion” in the cone inner segments of Tupaia represents an
extreme adaptation to diurnality and, thus, predestines Tupaia belangeri for follow-up
studies on this problem. Correspondingly, Joffe et al. (2014) demonstrate
that, in the cones of Tupaia belangeri, nucleoli with high refractive indices are constantly
situated at the inner pole of the cone nucleus and may act as a “second
lens”.
Irrespective of the question to which extent megamitochondria in the cone
inner segments of Tupaia belangeri provide energy equivalents and/or assist in guiding
light, mitochondria are relevant for studies in age research. This holds
especially true for megamitochondria which facilitate refined investigations
of the mitochondrial DNA (Primmer, 2002), all the more so as the complete
mitochondrial genome of Tupaia belangeri has already been analyzed (Schmitz et al., 2000). In
the context of age research, other advantages of tree shrews, compared with
rodents, are their longevity and their phylogenetic status closer to humans
(Primmer, 2002).
Ciliogenesis in photoreceptor cells
Having completed our 3-D reconstructions of cone inner segments, we next
wanted to learn more about the mechanisms which regulate the highly ordered
immigration of mitochondria into the developing cone inner segments of
Tupaia belangeri. We discovered contacts between migrating mitochondria and groups of
microtubules originating from the pair of centrioles which is situated in
apicalmost parts of the inner segments. Obviously, these microtubules serve
as a guide for mitochondria (Fig. 3a, Knabe and Kuhn, 1996b). Only
thereafter does the “connecting cilium” spring from the apical centriole of
the microtubule-organizing center (MTOC) and transform into the
light-absorbing outer segment (Knabe and Kuhn, 1997, 1998a).
So far, a microtubule apparatus which supports the migration of mitochondria
into the developing cone inner segment has not been demonstrated in any
other vertebrate. Nevertheless, similar arrangements of microtubules exist
during the redistribution of mitochondria in developing Müller cells of
the rabbit retina (Germer et al., 1998). However, the observed pattern of
microtubules does not permit full-length guidance, and oxygen gradients may
play the major role in this context. For another example, a structure
resembling the Drosophila fusome which is involved in anchoring centrioles
and organizing the primary mitochondrial cloud around the centriole was
found during female germline cyst development in Xenopus laevis (Kloc et al., 2004).
Mitochondria also appear to be moved by microtubules during merozoite
assembly in Plasmodium falciparum (Hopkins et al., 1999), and mitochondrial dysfunction results
from abnormal microtubules in cytoplasmic male sterility of higher plants
(Li et al., 2014, in conjunction with findings of Zhang et al., 2009).
In the cones of Tupaia belangeri, onset of ciliogenesis precedes the outgrowth of the inner
segment by about half the gestation time. Up to 1 week after birth, the
two centrioles responsible for ciliogenesis are situated centrally and,
thus, reside in an ideal position to support the immigration of mitochondria
into the developing inner segment (Fig. 3a). Only after this do the two
centrioles as well as the associated connecting cilium shift from
central to excentric positions (Figs. 2c, 3a) and, most astonishingly, in
hundreds of neighboring cones to one and the same side of the inner segment
(Knabe and Kuhn, 1997). Studies of this type help to improve our
understanding (1) of protein sorting, targeting and trafficking in
photoreceptor cells (Pearring et al., 2013); (2) of the procedures and
meaning underlying the apical positioning of primary cilia (Kong et al.,
2013; Wheway et al., 2014); and (3) of general aspects of ciliogenesis and
cilium-based diseases (Insinna and Besharse, 2008; Gakovic et al., 2011).
However, our major discovery in this context remains the coordinated
relocation of the connecting cilium to identical excentric positions (Knabe
and Kuhn, 1997), which also takes place in zebrafish (Ramsey and Perkins,
2013). In the adult zebrafish, cilia are situated asymmetrically on the cell
edge nearest to the optic nerve in red-, green-, and blue-sensitive cones, but
not in ultraviolet-sensitive cones or rods. Thus, motile as well as immotile
cilia demonstrate patterns of planar polarity (Ramsey and Perkins, 2013).
However, it is still unclear how this type of planar polarity is
established in cones and what its functional impacts are. This may be about
to change in view of the exciting new discovery that, in kidney epithelial
cells, primary cilia (9 + 0 cilia) undergo active fluctuations in the
absence of dyneins (Battle et al., 2015).
Cone outer segments
In the (for now) last ultrastructural work our group has published on the
development of photoreceptor cells, focus was given to the formation of
disks in the cone outer segments (Knabe and Kuhn, 1998a, also for review).
Morphogenesis of the membranous disks which contain the visual pigments has
been explained differently so far. According to the first hypothesis, disks arise
from vesicles which pinch off from the basal cell membrane of the outer
segment and then fuse and flatten (Obata and Usukura, 1992; Usukura and
Obata, 1995). In this model, continuity between the interior of the disks and
the extracellular space, as seen in mature cones, results from the secondary
fusion between the disks and the cell membrane of the outer segment. In
contrast, disks in the developing cone outer segments of Tupaia belangeri develop between
the apposed membranes of two neighboring “basal evaginations” (Steinberg
et al., 1980; Eckmiller 1987, 1990) rich in cytoplasm, which protrude from
the position of the eccentrically localized ciliary axoneme to the opposite
side (Fig. 3b, c). Consequently, from the very beginning, the interior of
newly formed disks opens to the extracellular space. The reservation must be
made that, in both scenarios, the interior of the disks represents
incorporated extracellular space. The only difference seems to be a
heterochrony of the formation of the disks and their internalization. Later,
Holcman and Korenbrot (2004) demonstrated that different patterns of
disk formation in cones and rods, the latter finally revealing disks not
joined with the plasma membrane, are responsible for the different diffusion
characteristics of the excitation signal cGMP in cones and rods,
respectively.
Horizontal cells
Another project looked at whether retinal neurons, with the exception of
neurovascular contact points serving vasoregulation, are completely
separated from the basal lamina of capillaries by macroglial cells
(astrocytes and Müller cells). Using a combination of transmission
electron microscopy, immunohistochemistry, and lectin histochemistry, the
structural links between endothelial cells, pericytes, glial cells, and
neurons were studied in the four vascular layers of the retina of adult
Tupaia belangeri. Much to our surprise, an incomplete macroglial ensheathment of the
capillaries was observed, most notably in the outer capillary layers 1 and 2
(Fig. 4). In capillary layer 1, which is located between the inner nuclear
layer and the outer plexiform layer, these “gaps” were filled with the
perikarya and electron-lucent processes of horizontal cells that, in single
sections, ensheathed up to approximately 9 / 10 of the capillary
circumference (Knabe and Ochs, 1999). We therefore postulated that “current
concepts of retinal function and pathology, which are based on the
assumption that retinal vessels are strictly isolated from retinal neurons,
at least in Tupaia, might deserve reconsideration”.
To define the scope of our findings more accurately, in a second step, an
unbiased stereological method was used to determine the extent of basal
lamina occupied by macroglial Müller cells and non-macroglial cells,
respectively, in the three outer capillary layers of the central retina of
adult Tupaia belangeri (Ochs et al., 2000). It turned out that the mean (standard deviation)
percentage surface coverage by non-Müller cell processes was 46.8
(15.3) % (layer 1), 3.0 (2.1) % (layer 2), and 0.3 (0.3) % (layer 3).
In most cases, capillary-contacting non-Müller cells in capillary layer
1 belonged to horizontal cells of the mammalian type A (Knabe and Kuhn,
2000).
Based on immunohistochemical and confocal microscopic techniques, extensive
vascular contacts of retinal horizontal cells proved to be present also in
rats and mice and, thus, “appear to be a more common theme for these
neurons than previously appreciated” (Mojumder, 2008). Equally important are
efforts to decipher the functions as well as the possible pathological
consequences of the vascular contacts of horizontal cells. On the assumption
that retinal cilia are capable of detecting potentially harmful changes in
the extracellular environment, Kim et al. (2013) have studied the presence
of cilia in the retina of adult mice. It could be shown that ciliary markers
(Arl13b, a small GTPase localized on cilia membrane; acetylated
alpha-tubulin; adenyl cyclase III) are expressed, among other places, by the
processes of horizontal cells which, due to their extensive neurovascular
contacts (Knabe and Ochs, 1999; Mojumder, 2008), are predestined for
monitoring and controlling the extracellular milieu.
Pathological situations in which vascular contacts of horizontal cells play
a role have been demonstrated in mice with oxygen-induced retinopathy, where
links appear to exist between neurovascular cell injury and the arginase
pathway (Suwanpradid et al., 2014). Beforehand, Ahuja et al. (2005) aimed to
clarify whether and how glutathione S transferase (GST) helps to protect
photoreceptor cells. Using rd1/rd1 mice containing an insertion of viral DNA
in the β-subunit of the cGMP phosphodiesterase gene, reduced amounts
of α- and µ-GST were found in Müller cell end feet as well
as in large caliber horizontal cell fibers. Consequently, Ahuja et al. (2005)
speculated that, in wild-type mice, secreted GST may protect the
retina against toxic molecules penetrating through the capillaries and
invading the adjacent tissue. Alternatively, GST released from Müller
cells and/or horizontal cells may interact with reduced glutathion and
proteins adhering to the surface of photoreceptor cells and, thus, may help
to bring about their survival. Also of particular interest are the research
contributions made by Park et al. (2003a), who have studied the patterns of
apoptotic death among photoreceptor cells in streptozotocin-induced diabetic
rat retina. These authors demonstrate degenerative changes of horizontal
cell processes already after 1 week, and this, most probably, happened
thanks to their extensive vascular contacts, which make them “sensitive to any minute alteration in the capillaries”.
Given the presumed impact of neurovascular contacts of horizontal cells on
health and disease, it is actually staggering how little we know about the
development of these contacts. Such investigations are the more necessary
since Bosco et al. (2005) have observed a coordinate developmental switch of
the expression of aquaporin-4 (AQP4) and inwardly rectifying K+ channels
(Kir4.1) from horizontal cells to Müller cells in the retina of mice as
soon as they can see for the very first time. Based on the premise that AQP4
and Kir4.1 help to clear extracellular K+ and water from the synaptic
layers, Bosco et al. (2005) suggest that differentiating horizontal cells
“may contribute to early retinal homeostasis” and, possibly, “fulfill an
archetypal glial function”. Expectations are high as to how the observed
switch in the expression patterns of AQP4 and Kir4.1 correlates with the
development of the extensive vascular contacts of retinal horizontal
cells.
“Starburst” amacrine cells
Next we have investigated the development of cholinergic amacrine cells in
the retina of Tupaia belangeri (Knabe et al., 2007). Through the optimization of standard
immunohistochemistry protocols, cholinergic amacrine cells which play key
roles “in originating retinal directional selectivity and optokinetic eye
movement” (Yoshida et al., 2001) could be detected 2 weeks earlier than
had been reported previously (Sandmann et al., 1997). This helped to
demonstrate that, in mammals, two mirror-imaged subpopulations of
cholinergic amacrine cells are derived from a single population of precursor
cells (Fig. 5). Furthermore, refined knowledge of the similarities and
dissimilarities which characterize the development of “orthotopic”
starburst amacrines in the inner nuclear layer and “intentionally
displaced” starburst amacrines in the ganglion cell layer facilitates
differential diagnosis of these regular subpopulations from erroneously
migrating “misplaced” starburst amacrines (Pérez de Sevilla Müller
et al., 2007; for a comprehensive review, see Famiglietti and Sundquist,
2010).
In the retinal inner plexiform layer of Tupaia belangeri, establishment of mirror-imaged
directionally selective circuits is initiated by the dendrites of
cholinergic amacrine cells. These dendrites provide the scaffold for the
dendrites of directionally selective ganglion cells which contact starburst
amacrines with a delay (Knabe et al., 2007). Most probably, proper
development of these networks depends on the presence of stable
neurofilaments resulting from the coexpression of neurofilament protein M
(NF-M, 150 kDa) and α-internexin in the dendrites of starburst
amacrines (Fig. 6). As soon as the earliest functional synapses have formed
in the inner plexiform layer (Foelix et al., 1987), both the dendrites of
starburst amacrine cells and the dendrites of directionally selective
ganglion cells downregulate NF-M and/or α-internexin (Knabe et al.,
2007). The obvious question to ask here is whether the transient
coexpression of these two neurofilament proteins not only stabilizes the
dendrites of starburst amacrines and ganglion cells but also somehow
promotes their mutual recognition. In the long term we are aiming to
clarify whether the expression of different combinations of neurofilament
proteins in the retina has anything to do with the selective vulnerability
of certain of the neuronal classes which, for example, has been observed
during diabetic retinopathy (Park et al., 2003b; Gastinger et al., 2006; Kern
and Barber, 2008).
The temporary occurrence of α-internexin during defined
developmental periods, as seen in the retina of Tupaia belangeri (Knabe et al., 2007),
suggests that α-internexin might play a role in neuroplasticity.
Under this premise, Liu et al. (2013) have studied the expression patterns
of α-internexin in neuronal lineages of the developing chick retina.
It turned out that, at least in early phases of development, chick embryos
demonstrate a much broader expression profile for α-internexin
compared with Tupaia belangeri (photoreceptor cells, horizontal cells, bipolar cells,
amacrine cells, ganglion cells), whereas permanent expression is restricted
to ganglion cells, amacrine cells, and horizontal cells. The functional
meaning of interspecific differences regarding the physiological expression
of α-internexin needs to be clarified in follow-up studies.
Knowledge of these expression patterns is also relevant under pathological
conditions, e.g., in a spontaneous equine model of autoimmune uveitis where
vitreal IgM autoantibodies target NF-M in neuronal processes of the retina
(Swadzba et al., 2012).
Whether the developing axons of retinal ganglion cells cross the chiasmatic
midline or stay ipsilaterally depends, among other factors, on the
interactions with “guide post cells”. Studies on embryonic mice have
revealed specialized radial glial cells as well as neurons of the
anterobasal nucleus which express different sets of molecules capable of
either repelling or attracting ganglion cell axons close to the brain
midline (for reviews, see Williams et al., 2004; Jeffery and Erskine, 2005;
Petros et al., 2008). Our observations on this point disprove the widely
favored hypothesis that previous findings in mice are representative for all
placental mammals. In the studied embryos of Tupaia belangeri, ipsilateral axons turn back
towards their site of origin already in prechiasmatic parts of the optic
nerve (Fig. 7a, b, Knabe et al., 2008; for adult Tupaia also see Jeffery et
al., 1998), thus resembling marsupials (Taylor and Guillery, 1994; Harman and
Jeffery, 1995; MacLaren, 1998). Consequently, it seemed to us rather
improbable that axonal pathfinding in the optic chiasm of Tupaia should be
primarily attributable to midline signalling. Actually, we noticed that the
guidance of ipsilateral axons depends on “glial arches” (Fig. 7c, d) which
are situated, bilaterally symmetrically, at the transition of the optic
nerve to the optic chiasm and which originate from the lateral
subventricular zones adjacent to the third ventricle (Knabe et al., 2008).
It turned out that, among placental mammals, segregation of ipsilaterally
and contralaterally projecting axons by guide post cells at a distance from
the chiasmatic midline, first reported in Tupaia belangeri (Knabe et al., 2008), is by far
not the exception to the rule. Thus, Jeffery et al. (2008) postulated that a
similar zone of decision-making should exist in Callithrix jacchus. The particular importance
of the observations made in Tupaia belangeri (Knabe et al., 2008) and marmosets (Jeffery et
al., 2008) lies in the fact that a similarly structured optic chiasm appears to
exist in man. That also explains why, in man, developmental loss of one eye
does not adversely affect the axonal projections of the remaining one –
quite different from rodents where segregation of axons from both eyes
depends on mutual interactions at the brain midline (Neveu et al., 2006).
Accordingly, Tupaia belangeri (Knabe et al., 2008) and marmosets (Jeffery et al., 2008) are
appropriate models for studying the mechanisms which regulate axonal
pathfinding in the visual system of man.
The joint research focus of Cordula Renate Malz, Hans-Jürg Kuhn, and
colleagues was on the development of the olfactory systems of Tupaia belangeri. Additional
studies were carried out on structure–function relationships in the
pituitary gland and cerebellum.
Lectin binding
As a first step, Malz et al. (1999) investigated lectin-binding sites in the
vomeronasal organ and in the olfactory epithelium. These findings support
the hypothesis that specific sets of glycoproteins contribute to the
histogenesis of the individual systems as well as to the recognition and
transduction of olfactory/pheromonal stimuli. For example,
alpha-N-acetylgalactosamine is expressed in the vomeronasal nerve but not
in the olfactory nerve. Within the vomeronasal organ, alpha- and
beta-N-acetyl-D-glucosamine are simultaneously present in the presumed
regeneration zone. Finally, it appears possible that pregnancies have an
influence on the abovementioned processes in the vomeronasal organ, as
revealed by the different expression patterns of Dolichos biflorus lectin in pregnant and
non-pregnant Tupaia belangeri.
Lectin panels provided by Malz et al. (1999) and others help to make a
distinction between animals with functional or non-functional vomeronasal
organs. Thus, markedly different overall patterns of lectin immunostaining
were observed in vestigial vomeronasal organs of humans and chimpanzees
compared with chemosensory vomeronasal organs in other primates (Kinzinger
et al., 2005). Furthermore, knowledge of the lectin-binding patterns in the
olfactory and nasal epithelia is a prerequisite for lectin-mediated DNA
delivery during targeted mucosal immunization (Wang et al., 2005).
Thereafter, focus was placed on the expression patterns of calretinin, which
belongs to the EF-hand family of calcium-binding proteins. According to
Heizmann and Braun (1992) and Schwaller (2014), calretinin is involved in
intracellular calcium signalling, mediates the calcium-buffering capacity of
cells, and protects neurons against calcium overload. We aimed to clarify –
for the first time extensively – whether different expression patterns of
calretinin exist in the functionally different vomeronasal and main
olfactory systems. It turned out that calretinin is present in virtually all
vomeronasal receptor cells and fibers (Fig. 8), but only in subsets of
receptor cells belonging to the main olfactory system (Malz et al., 2000).
This means that only certain of the olfactory qualities are perceived under
the influence of calretinin. Conversely, the number of
calretinin-immunopositive interneurons was much higher in the main olfactory
bulb compared with the accessory olfactory bulb (Fig. 9). Our observations
further suggest that structurally and functionally distinct subclasses of
output cells (mitral cells, tufted cells) and interneurons help to establish
a laminar organization of the external plexiform layer (EPL), which is
subdivided into a weakly calretinin-immunopositive superficial layer and a
strongly calretinin-immunoreactive deep layer (Malz et al., 2000).
Correspondingly, Kakuta et al. (2001) demonstrated that, in insectivores
(Suncus murinus) “the EPL is divided into the OSL [outer sublayer] and ISL [inner
sublayer] based on the different meshworks of CB[calbindin]-positive
neuronal processes (…), and based on the different densities of
CR[calretinin]-positive fibers”.
Our findings in Tupaia belangeri are required to clarify the
interspecific variability of calretinin expression (Pombal et al., 2002:
Lampetra fluviatilis; Castro et al., 2006: Danio rerio; Castro et
al., 2008: Salmo trutta fario), and to facilitate comparison between the immunoreactive
patterns of calretinin and other calcium-binding proteins (Jia and Halpern,
2003: calbindin-D28k, rat; Jia and Halpern, 2004: calbindin-D28k,
parvalbumin, calretinin, Monodelphis domestica; Morona and González, 2008: calbindin-D28k,
calretinin, anuran and urodele amphibians; Morona et al., 2011:
calbindin-D28k, calretinin, Dermophis mexicanus; Kosaka and Kosaka, 2004: calbindin-D28k, rat,
mouse, tree shrew, bat, hedgehog, laboratory musk shrew, mole). However, it
must be pointed out that “the content of a particular calcium-binding
protein in a neuronal group is not a fully reliable criterion for
considering homologies” (Morona and González, 2008).
Knowledge of the expression patterns of calretinin and other calcium-binding
proteins can be successfully applied for detecting the effects of gene
mutations. Thus, as a consequence of lamination defects, an almost complete
breakdown of the physiological expression pattern of calretinin was observed
in the olfactory bulb of dlx5 (distal-less homeobox 5)-/- mice (Levi
et al., 2003). Testing panels of calcium-binding proteins also facilitates
functional studies of calcium-controlled processes, for example, in the
frameworks of pulse stimulation of isolated olfactory neurons with odors and
isobutylmethylxanthine/forskolin (Zhang and Delay, 2006) or following urine
stimulation of the mouse vomeronasal organ, which activates large-conductance
Ca2+-activated K+ channels (Zhang et al., 2008). Finally, a good
understanding of the expression patterns of calcium-binding proteins helps
to find answers to evolutionary biological problems, e.g., when analyzing the
vomeronasal type 1 receptor (V1R) family (Young et al., 2010). One of the
interesting results of this study is that “almost all of the species with
large V1R repertoires have well-developed vomeronasal organs and/or AOBs
[accessory olfactory bulbs]”.
We subsequently investigated the expression patterns of calretinin and
olfactory marker protein (OMP) in the developing vomeronasal and main
olfactory systems of Tupaia belangeri (Malz et al., 2002). In the other mammals studied so
far, calretinin expression levels start off very low at birth but then
rapidly increase during postnatal development (Bastianelli et al., 1995;
Kimura and Furukawa, 1998). Thus, it came to us as a surprise that, in
Tupaia belangeri, strong expression of calretinin in receptor cells, nerve fibers, many
interneurons, and projecting neurons of both olfactory systems was already
present during embryonic development (Fig. 10). As a result, subpopulations
of receptor cells of the vomeronasal system can now be distinguished
prenatally by their profoundly differing degrees of calretinin expression
(Malz et al., 2002).
Our findings in Tupaia belangeri have provided supplemental information for studies on the
growth and maturational characteristics of the vomeronasal complex in
nocturnal strepsirhines insofar as these are revealed by the expression
pattern of OMP (Garrett et al., 2013). Similarly, Shimp et al. (2003) have
investigated the ducts leading to the vomeronasal organ in order to identify
differences regarding the perinatal functionality of the vomeronasal system
in primates (Microcebus murinus), mice, and insectivora. Compared with the data available for
adult animals, much less is known about the expression patterns and
functions of calcium-binding proteins in the developing olfactory systems
(e.g., Halpern and Martínez-Marcos, 2003: mammals, VNO; Castro et al.,
2008: Salmo trutta fario).
Terminal nerve
Malz and Kuhn (2002) have further demonstrated, for the first time in a
placental mammal, the embryonic development of calretinin- and
Phe-Met-Arg-Phe (FMRFamide)-immunoreactive neurons in the terminal nerve
(“cranial nerve zero”; for a review, see Vilensky, 2014). This nerve is a
“diffusely organized system of neurons” which emigrate from the olfactory
placode and, in all jawed vertebrates, finally reside “within the nasal
cavity and rostral forebrain” (Wirsig-Wiechmann et al., 2002). It runs in
close vicinity to the main olfactory and vomeronasal nerves, contains
compact ganglia, and also exists in humans (de Vries, 1905: cited in Larsell,
1950; Brookover, 1914; Johnston, 1914). Subpopulations of its neurons contain
neuropeptides, among others gonadotropin-releasing hormone (GnRH), which
modulate the activity of receptor cells (Wirsig-Wiechmann et al., 2002;
Vilensky, 2014).
In Tupaia belangeri, calretinin and the cardioexcitatory tetrapeptide FMRFamide – the latter
as early as GnRH – are expressed in different subpopulations of migrating
and ganglionic neurons (Fig. 11, Malz and Kuhn, 2002). Later, Park et al. (2003a)
demonstrated that, in Ambystoma mexicanum, FMRFamide dramatically increases the
magnitude of a voltage-gated inward current in the olfactory receptor cells.
In mouse olfactory sensory neurons, FMRFamide modulates potassium currents
(Ni et al., 2008), whereas FMRFamide-like peptides exert inhibitory effects
on the pacemaker activity of GnRH neurons in the freshwater tropical fish
Colisa lalia (Saito et al., 2010). Other findings in
Tupaia belangeri suggest that calretinin influences
the migration and differentiation of neurons which are associated with the
terminal nerve (Malz and Kuhn, 2002). In contrast, calretinin-immunoreactive
migrating cells are absent from the terminal nerve in the brown trout
(Salmo trutta fario; Castro et al., 2008).
Knowledge of the early pathways along which luteinizing hormone-releasing
hormone (LHRH)- and FMRFamide-immunoreactive neurons reach the forebrain
also helps in testing functional hypotheses. Thus, it turned out that, in
newborn marsupials (Macropus eugenii), these pathways are usually too immature to support
guidance to the pouch and nipple (Ashwell et al., 2008). Accordingly, at
birth, the degree of maturity of these olfactory pathways is not high enough
to allow olfaction-mediated behavior in platypus and echidnas, “two modern
monotreme lineages that have followed independent evolutionary paths from a
less olfaction-specialized ancestor” (Ashwell, 2012). Nevertheless, as in
Tupaia belangeri, a terminal nerve including ganglia is present already prior to birth.
Based on the previous work by Blanck (1983), Malz and Kuhn (1999) have
investigated whether invertebrate neuropeptides (in this case, FMRFamide)
have counterparts in the pituitary gland of mammals. In the pituitary gland
of Tupaia belangeri, FMRFamide is already present on embryonic day 27, and the adult
labelling pattern is established around embryonic day 41. Overall, the
findings of Malz and Kuhn (1999) indicate that FMRFamide contributes to the
regulation of releasing factors as well as to the secretion of hormones.
Furthermore, a subpopulation of FMRFamide-immunopositive cells is
demonstrated which migrate from the pars intermedia to the neural lobe. Most
probably, these cells represent invading basophils (Malz and Kuhn, 1999).
Interestingly, a complex innervation pattern of FMRFamide-immunoreactive
fibers was also found in the brain of Salmo trutta fario and, here, included moderate amounts
of FMRFamide-labelled fibers in the pituitary gland (Castro et al., 2001).
Cerebellum
Parasagittal compartments in the cerebellar cortex with precisely regulated
input and output characteristics are revealed by immunohistochemistry with
antibodies against zebrin I (Hawkes and Leclerc, 1989). In cooperation with
colleagues from the University of Calgary (Alberta, Canada) and the Riken
Brain Science Institute in Wako-shi (Saitama, Japan), C. R. Malz has
demonstrated that zebrin II (Brochu et al., 1990; epitope on the respiratory
isoenzyme aldolase C: Ahn et al., 1994)-immunoreactive parasagittal stripes and
transverse zones in the cerebellar cortex of Tupaia belangeri much more closely correspond
to those of primates, compared with rodents or lagomorphs (Sillitoe et al.,
2004). Confirmed by later findings in the laboratory mouse (Chung et al.,
2008), zebrin-II-labelled compartments in Tupaia belangeri are not seen as all-or-none
expression differences, but through differences in the intensity of
immunostaining (Sillitoe et al., 2004).
Other groups have subsequently studied zebrin-II-immunoreactive cerebellar
compartments in order to carry out the following investigations: (1) interspecific
comparison with the tammar wallaby (Macropus eugenii) (Marzban et al. 2012),
microchiropteran bats (Kim et al., 2009), hummingbirds (Aves: Trochilidae)
(Iwaniuk et al., 2009), chicks (Gallus domesticus) (Marzban et al., 2010),
pigeons (Columba livia) (Pakan et al., 2007; for an overview, see
Marzban and Hawkes, 2011); (2) visualization
of aldolase C with fluorescence through gene manipulation with the help of
aldolase C-Venus knock-in mice to facilitate studies on cerebellar
compartmentalization (Fujita et al., 2014); (3) presentation of parasagittal
stripes in the vermis which, complementary to zebrin II, are immunoreactive
for neurofilament H (Demilly et al., 2011); (4) identification of links
between the olivocerebellar projection and zebrin-immunoreactive
compartments in the laboratory mouse (Sugihara and Quy, 2007) and in marmoset
(Callithrix jacchus) (Fujita et al., 2010); (5) clarification of the role played by the
helix-loop-helix (HLH) transcription factor early B-cell factor 2 (EBF2)
(Croci et al., 2006); and (6) evaluation of the cerebellar connectivity in
spinocerebellar ataxia type 1 (Solodkin et al., 2011).
Apoptosis and macrophages in the developing forebrain and eyes
The second main research area of Wolfgang Knabe and colleagues, whose roots
date back to the former anatomical department of Hans-Jürg Kuhn,
continued previous projects on the retina, then served as a bridge between
the retina and the forebrain, and, thereafter, was successively expanded to
include the entire brain, spinal cord, neural crest, and the placodes.
As conflicting statements had been published with regard to the patterns and
functions of apoptosis in the early developing forebrain and eye, we decided
to further study this issue using 3-D reconstructions. For this purpose
“semithin” serial sections, meaning sections from 1 to 2 µm in
thickness, were taken from young embryos of Tupaia belangeri. In contrast to the work of
earlier authors which had postulated the ubiquitous existence of isolated
foci of cell death, we observed a spatiotemporally continuous process with a
sharply defined maximum and characteristic, long-drawn-out “bands of
apoptotic cells”. Most, if not all, isolated apoptotic foci – which
previously had been reported and, partly, interpreted as species-specific
characters by others – turned out to topographically represent “segments”
of a maximally extended band of cell death resembling that found in Tupaia belangeri. We,
therefore, concluded that at least similar band-like apoptotic processes
should occur in the embryonic forebrain and eyes of other vertebrates (Knabe
and Kuhn, 1998b; Knabe et al., 2000).
In Tupaia belangeri, the maximally extended band of apoptotic cells runs from the dorsal to
the ventral midline of the prosencephalon (Fig. 12a, c, e, g). From the
approximate future position of the optic chiasm, this band continues,
bilaterally symmetrically, to the lateral wall of the diencephalon, to the
optic stalk, and, finally, to the ventral, lateral, and dorsal walls of the
invaginating optic vesicle (Knabe et al., 2000). Supported by additional
other evidence (Golden et al., 1999), the long-drawn-out band of
developmental cell death discovered by us appears to contribute to the
regulation of late bilateralization processes of the forebrain which,
finally, help to establish paired hemispheres of the forebrain as well as
paired olfactory and optic anlagen. Consequently, disturbances of the
physiological pattern of apoptosis may cause holoprosencephaly and cyclopia,
or related malformations.
Given the fact that professional macrophages can eliminate dead cells or
trigger apoptosis (Frade and Barde, 1998; Diez-Roux et al., 1999; for a
review, see Pont-Lezica et al., 2011), we were interested to learn whether
macrophages influence apoptosis in the early developing forebrain and eyes
of Tupaia belangeri. It came out that, in Tupaia, earliest macrophages are present in the
blood islands of the yolk sac. Thereafter, macrophages emigrate from the
perineural vessels, invade the anlagen of the forebrain and eyes from their
pial/external surfaces, transmigrate the neuroepithelial wall, and, finally,
arrive in the developing brain ventricles (Fig. 13a–d, Knabe and Kuhn, 1999).
An early appearance of macrophages was also demonstrated in the brain and
optic anlagen of zebrafish (Phelan et al., 2005). These macrophages express
members of the evolutionarily conserved Toll-like family (zfTLR3, zflRAK-4,
and zfTRAF6) which is of relevance for the innate immune system. Resembling
our findings in Tupaia belangeri, primitive macrophages invade the zebrafish brain prior to
its vascularization (for a review, see Traver et al., 2003). However, whether
macrophage colonization of the brain follows the same principle in mammals
and birds remains a matter of debate. Thus, in chicks, Kurz et al. (2001)
found evidence that “blood-borne cells do not contribute to the intraneural
macrophage population of the embryonic CNS” – at least during the time
window which can be studied in chick–quail parabiosis.
Standardized counts in the embryos of Tupaia belangeri revealed that “waves of
macrophages”, which all in all reflect their invasion route, occur
sequentially in the different perineural compartments and, with a delay, in
the neuroepithelium (Fig. 13e). Our 3-D reconstructions further demonstrate
that macrophages rapidly invade pre-existing bands of apoptotic cells
(Fig. 12). There is no indication for the induction of large-scale apoptosis by
macrophages (Knabe and Kuhn, 1999; Knabe et al., 2000). A close association
between cell death and macrophages was also found in early phases, but not
in late phases, of mouse retinal development (Santos et al., 2008).
The question whether, in vertebrates, a “canon” of apoptotic patterns
exists in certain phases of brain development has lost none of its
immediacy. This applies all the more so since, in particular, the functions
of apoptotic events in early developmental periods are still poorly
understood. Bejarano-Escobar et al. (2013), for example, are studying the
small spotted catshark Scyliorhinus canicula, first because elasmobranchs “occupy a key
phylogenetic position as an out-group to osteichthyans” and, second, because
catsharks grow slowly and have large eyes, the latter properties being of
great benefit for the analysis of rapidly running apoptotic processes. It
turned out that apoptotic events in dorsal parts of the optic vesicle –
initially judged to be a specific property of the chick (García-Porrero et
al., 1984) and, later, demonstrated in Tupaia belangeri (Knabe and Kuhn, 1998b; Knabe et al.
2000) – are also present in the catshark (Bejarano-Escobar et al., 2013).
Correspondence between Tupaia belangeri and Scyliorhinus canicula also exists regarding clusters of apoptotic
cells in the anterior wall of the developing lens as well as in the future
position of the optic chiasm where apoptosis probably contributes to the
ventral shifting of the optic stalk. However, no match was found for the
“suboptic necrotic center” (SONC, Källén, 1965; Navascués et
al., 1988), which, in the vicinity of the optic chiasm, is particularly
conspicuous in Tupaia belangeri. Fully in line with this, no chronotopographical
relationship between macrophages and apoptotic cells could be demonstrated
in the catshark (Bejarano-Escobar et al., 2013). For these and other reasons,
Francisco-Morcillo et al. (2014) conclude that, in the developing visual
system, “dying cells show similar but not identical spatiotemporally
restricted patterns in different vertebrates”. The same appears to hold
true for macrophages, which may or may not contribute to the elimination of
apoptotic cells.
For a long time, 3-D reconstruction techniques have enriched the treasury of
embryological research. It therefore comes as no surprise that many of the
works carried out by former students of Hans-Jürg Kuhn still involve 3-D
reconstructions (e.g., Schunke and Zeller, 2010; Washausen and Knabe, 2013).
However, the need for processing ever bigger data sets, which in our case
contain information from large embryonic surfaces as well as from millions
of single cells, required a fundamental revision of our pre-existing
reconstruction techniques (Knabe and Kuhn, 1996a). Similarly, elaborate
atlases on prenatal organ development have been generated by other
work groups (e.g., Radlanski et al., 2010).
For our purposes, we have established an AutoCAD-based reconstruction system
(Knabe et al., 2000; Süss et al., 2002: Fig. 14a–d), which subsequently was
optimized with the help of the Deutsche Forschungsgemeinschaft (KN 525/1-1,
1-2, BR 1185/4-1). As a first step, the novel high-resolution scanning
system “Huge Image” was developed in cooperation with ZEISS (Süss et
al., 2000, 2002; Fig. 14e). In line with this trend, Ma et al. (2008a, b)
have established “Autostitch” to automatically combine multiple images of
microscopic sections “to produce a panorama of larger image” without any
time-consuming user input. Meanwhile, abundant applications of mosaic-like
scanning techniques are found in biological research, e.g., in cortical
mapping (Schleicher et al., 2009).
In a second step, we then developed a novel procedure for the alignment of
(resin-embedded) serial sections which is largely independent of internal
embryonic fiducial markers (Fig. 15). This method is especially suitable for
reconstructing small embryos in utero as well as genetically modified and
potentially malformed embryos which may lack relevant internal fiducial
markers, e.g., symmetrically aligned organ rudiments and/or midline
structures (Fig. 16, Knabe et al., 2002).
When resin-embedded tissue blocks are not available, sections from
paraffin-embedded tissue may alternatively be processed by the tissue array
procedure. Here, tissue cores from a donor block are embedded as fiducial
markers at the periphery or inside the target tissue (Bussolati et al.,
2005). To avoid complex realignment procedures, large-volume 3-D
reconstruction may be coped by mounting samples on a high-precision
translation stage and acquiring optical sections from the stained block
surface which is sequentially removed with an ultramiller (Gerneke et al.,
2007). Alternatively, non-deparaffinized thick sections which preserve
mutual relationships of tissue components may be used for 3-D reconstruction
with the help of either fluorescence or confocal microscopy (Jirkovská
et al., 2005).
Finally, our cooperation with Guido Brunnett (Technische Universität
Chemnitz) resulted in the development of a substantially faster
reconstruction technique which is based on triangulation algorithms
(Brunnett et al., 2003). Further joint projects led to improvements regarding
(1) data processing, (2) calculation of the reconstruction, (3) post-processing,
and (4) visualization (Kienel et al., 2008). In its current
configuration, our reconstruction system calculates large embryonic
surfaces, for example the outer wall of the brain and spinal cord, within
just a few seconds.
Midbrain
By application of the optimized reconstruction system we were able to
demonstrate that long-drawn-out bands of apoptotic cells are present not
only in the forebrain but also in all other major divisions of the brain.
For example, apoptotic events which in Tupaia belangeri possibly contribute to forebrain
bilateralization (Knabe et al., 2000) are transiently connected to a band of
dead cells in the dorsal midline of the midbrain. Additionally, there is
clearly continuity with so-far-undescribed, transversely oriented bands of
cell death which, bilaterally symmetrically, run at the boundary between
midbrain and synencephalon (Fig. 16). Possible functions of these transverse
bands may include boundary formation between developing diencephalic and
mesencephalic regions and/or the elimination of precursor cells of the
mesencephalic trigeminal nucleus which, in mice, is protected by the
embryonic erythropoietin system (Knabe et al., 2002, 2004a).
Previously undescribed patterns of apoptosis were also found in the
rhombomeres of Tupaia belangeri (Knabe et al., 2004b). We wished to clarify whether
segment-specific large-scale apoptosis, first noted in the chick (Lumsden et
al., 1991; Jeffs et al., 1992; Graham et al., 1993, 1994; Ellies et al., 2000),
is in fact generally absent from the rhombomeres of mammals (Trainor et al.,
2002). Our reconstructions clearly rebut this presumption. Firstly, several
identical key elements of a strictly spatiotemporally regulated sequence of
apoptotic events are present in chick embryos as well as in Tupaia belangeri (Fig. 17).
Secondly, again in line with previous findings in the chick, large-scale
apoptosis in dorsal parts of rhombomere 3 and, with a delay, in rhombomere 5
occurs in parallel with the delamination of neural crest cells which, in the
rostrocaudal direction, proceeds from rhombomeres 2 to 4 to 6 (Figs. 17,
18). These findings suggest that apoptosis in rhombomeres 3 and 5
predominantly eliminates premigratory neural crest cells and thereby helps
to generate crest-free spaces which separate neural crest streams adjacent
to the even-numbered rhombomeres. Obviously, additional factors are in place
to maintain the stereotypical pattern of three spatially segregated streams
of neural crest cells, for example, local cell-to-cell and long-range
cell–environment interactions (Teddy and Kulesa, 2004; for a review see
Theveneau and Mayor, 2012). Thirdly, except for dorsal apoptosis, rhombomeres
3 and 5 of the tree shrew hindbrain also contain dorsoventrally oriented
apoptotic bands (Figs. 17, 18). They may eliminate precursors of neural
crest cells which, by transplantation experiments, have been identified in
these ventral positions (Sechrist et al., 1995). Alternatively, these bands
of apoptotic cells may contribute to the fact that onset of neurogenesis in
the odd-numbered rhombomeres occurs with a delay, compared with the
even-numbered rhombomeres (Lumsden and Keynes, 1989; Eickholt et al., 2001;
Knabe et al., 2004b).
Given the fact that, in Tupaia belangeri, premigratory neural crest cells are subjected to
apoptotic selection, we wondered whether premigratory cells in neurogenic
placodes which also contribute to the formation of cranial ganglia are
“checked” in a similar fashion (Fig. 19). This hypothesis could be
confirmed on the example of the epibranchial placodes (Washausen et al.,
2005). In Tupaia belangeri, a rostrocaudally oriented apoptotic wave passes through the
combined anlagen of the otic placode and all three epibranchial placodes,
and it supports three major morphogenetic steps (Fig. 20): (1) the segregation
of individual placodes from larger anlagen, (2) the elimination of
subpopulations of premigratory epibranchial neuroblasts along dorsoventral
gradients, and (3) the ultimate elimination of the epibranchial placodes
after the completion of neuroblast delamination.
Studying the morphogenesis of epibranchial placodes, we could also achieve
another research objective, namely to demonstrate spatiotemporal
interactions between large-scale apoptosis and proliferative events (Fig. 20).
Subsequent tests will aim to clarify the regulation as well as the
functions of these so-far-undescribed interactions. Interestingly, these
interactions also affect the otic placode which, under the influence of
fibroblast growth factor (FGF) signals, shares a common zone of origin with
the epibranchial placodes (Washausen et al., 2005: Tupaia belangeri; Sun et al., 2007:
zebrafish; Sanchez-Guardado et al., 2014: chick).
In connection with these investigations, our 3-D reconstructions unexpectedly
revealed structural equivalents of hypobranchial placodes which, in Tupaia belangeri, are
eliminated by apoptosis (Washausen et al., 2005). Previously, such neurogenic
placodes which are situated ventrocaudal to the pharyngeal pouches and
generate functionally unexplained ganglia had been exclusively found in
amphibians (Schlosser, 2006). Neurogenic zones in ventral parts of the surface
ectoderm are also interesting from another point of view. In amphioxus
(cephalochordates), presumed precursors of sensory neurons, unlike the later
placodal cells, do not delaminate from dorsal, but from ventral parts of the
surface ectoderm. Consequently, these precursor cells – which, like
hypobranchial placodes in amphibians (Schlosser, 2003), express delta – may
represent the prototype of placode-derived neurons of the vertebrate cranial
ganglia (Rasmussen et al., 2007).
Naturally we wished to learn whether spatiotemporally regulated waves of
apoptotic and proliferative events also play significant roles during the
morphogenesis of other (neurogenic) placodes which segregate from the
U-shaped panplacodal primordium (Streit, 2007; Schlosser, 2010; Saint-Jeannet
and Moody, 2014). This hypothesis could be fully confirmed on the example of
the trigeminal placode (Obermayer, 2009; Knabe et al., 2009: Fig. 21). It
further emerged that even neuroblasts which migrate from the trigeminal
placode to the developing trigeminal ganglion are subjected to apoptotic
selection.
Our 3-D reconstructions of the trigeminal placode were also instructive with
regard to the structural composition of this placode, which, in Tupaia belangeri, differs
from all other placodes because of its diffuse texture (Fig. 22, Knabe et
al., 2009). Precisely such a kind of texture as well as the striking
positional changes of the vaguely delimited but contiguous trigeminal field
observed in Tupaia belangeri also characterize the human trigeminal placode (Müller and
O'Rahilly, 2011), which, again, underlines the significance of
the Tupaia model.
In the past 15 years, our knowledge on the panplacodal primordium and its
derivatives has enlarged explosively. After the discovery of the basic
molecular cascades which determine general and/or specific cell fates (for
review, see Schlosser, 2006), brand new hypotheses on the roles of cell fate
changes, local sorting-out processes, and massive cell movements await
further examination (Breau and Schneider-Maunoury, 2014). Other important
issues still in need of clarification are the molecular regulation and the
very exact functions of large-scale apoptosis first observed during the
morphogenesis of placodes in Tupaia belangeri. Fortunately, almost identical apoptotic
patterns contribute to the development of epibranchial placodes in mice
(Washausen and Knabe, 2013), which facilitates future experimental approaches. Edited by: E. Fuchs Reviewed by: two anonymous referees
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