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Dorsoventral Patterning of the Brain: A Comparative Approach

* and *.

* Corresponding Author: Institute of Genetics, University of Mainz, D-55099 Mainz, Germany. Email: urbach@uni-mainz.de; technau@uni-mainz.de

Development of the central nervous system (CNS) involves the transformation of a two-dimensional epithelial sheet of uniform ectodermal cells, the neuroectoderm, into a highly complex three-dimensional structure consisting of a huge variety of different neural cell types. Characteristic numbers of each cell type become arranged in reproducible spatial patterns, which is a prerequisite for the establishment of specific functional contacts. Specification of cell fate and regional patterning critical depends on positional information conferred to neural stem cells early in the neuroectoderm. This chapter compares recent findings on mechanisms that control the specification of cell fates along the dorsoventral axis during embryonic development of the CNS in Drosophila and vertebrates. Despite the clear structural differences in the organization of the CNS in arthropods and vertebrates, corresponding domains within the developing brain and truncal nervous system express a conserved set of columnar genes (msh/Msx, ind/Gsh, vnd/Nkx) involved in dorsoventral regionalization. In both Drosophila and mouse the expression of these genes exhibits distinct differences between the cephalic and truncal part of the CNS. Remarkably, not only the expression of columnar genes shows striking parallels between both species, but to some extent also their genetic interactions, suggesting an evolutionary conservation of key regulators of dorsoventral patterning in the brain in terms of expression and function.

Introduction

The central nervous system (CNS) in Drosophila and in vertebrates can be subdivided into two main portions, a truncal part (ventral nerve cord (VNC) in Drosophila and spinal cord in vertebrates) composed of repetitive segmental units and an anterior part, the brain, exhibiting a less overt segmental composition (Fig. 1).

Figure 1. Schematic representions of the morphology and subdivision of the embryonic CNS in Drosophila (A-C) and vertebrates (D-F).

Figure 1

Schematic representions of the morphology and subdivision of the embryonic CNS in Drosophila (A-C) and vertebrates (D-F). (A) Segmental topography of the Drosophila embryo at the phylotypic stage of development (stage 11). The scheme represents a flat (more...)

In Drosophila, the CNS develops from a bilaterally symmetrical sheet of neuroectodermal cells on the ventral side of the embryo. It gives rise to a fixed number of neural stem cells, called neuroblasts (NBs), which segregate to the interior of the embryo. NBs which form the VNC and brain descend from the truncal and procephalic neuroectoderm, respectively (Fig. 2).1,2 In vertebrates, the CNS forms from a bilaterally symmetrical neuroectoderm on the dorsal side of the embryo. The whole neuroectodermal sheet invaginates to form the neural tube, which develops into the spinal cord and brain. Accordingly, the differentiating NBs do not delaminate but maintain contact with the epithelial surfaces (for a review see ref. 3). Insect and vertebrate NBs divide reiteratively to give rise to specific types of neurons (motoneurons, interneurons) and glial cells.

Figure 2. Expression of Dpp/ BMP4 and Sog/Chordin as well as of the columnar genes support the inversion of the DV body axis.

Figure 2

Expression of Dpp/ BMP4 and Sog/Chordin as well as of the columnar genes support the inversion of the DV body axis. Simplified schemes of cross sections through the trunk of developing Drosophila and vertebrate embryos (indicated by frames in A,B; neurogenic ectoderm (more...)

In Drosophila, the border between neurogenic and nonneurogenic ectoderm becomes defined by two antagonistically acting extracellular factors encoded by short gastrulation (sog) and decapentaplegic (dpp). The homologous genes in Xenopus (vertebrates), Chordin and Bone morphogenetic protein 4 (BMP4), respectively, basically serve the same function.4 In both species, the region in which sog/Chordin is expressed forms the neuroectoderm. Since the neuroectoderm is ventral in arthropods but dorsal in vertebrates, this has supported the hypothesis that the dorsoventral (DV) body axis became inverted during chordate evolution. This concept suggests a monophyletic origin and thus, homology of the CNS in protostomes and deuterostomes.4-6

Remarkably, despite the clear structural differences in the mature CNS, corresponding DV subdomains within arthropod and vertebrate neuroectoderm express homologous genes (known as “columnar” genes; described below). This suggests that aspects of DV patterning of the neuroectoderm have been evolutionarily conserved as well, which further supports homology of the arthropod and vertebrate CNS.

The less complex truncal nervous systems in Drosophila and vertebrates (mouse, chick, frog) have provided useful models to study the mechanisms of patterning and the generation of neural cell diversity. Many of the developmental processes that underlie NB formation, cell fate specification and pattern formation have been extensively studied in this more accessible part of the CNS (for a review see e.g., refs. 7-11). How cell diversity and patterning are achieved in the brain of both animal phyla is less well understood.

Here, we compare recent findings on mechanisms that specify DV fates in the early (embryonic) brain of Drosophila and vertebrates and compare these mechanisms with those acting in the truncal CNS.

DV Patterning of the Truncal Part of the CNS in Drosophilaand Vertebrates

DV Patterning of the VNC in Drosophila

In Drosophila, the truncal neuroectoderm gives rise to the clearly metamerically organized VNC, which comprises 8 abdominal, 3 thoracic and 3 gnathal segmental units (neuromeres). The primordium of the VNC (neuroectoderm and NBs) is subdivided along the DV axis into adjacent longitudinal columns mainly by the activity of three homeobox genes (columnar genes). ventral nervous system defective (vnd) is expressed in the ventral, intermediate neuroblasts defective (ind) in the intermediate and muscle segment homeobox (msh; Drop [Dr]—FlyBase) in the dorsal neuroectodermal column (Fig. 3A).12-18 Onset of their expression is at the blastoderm stage.

Figure 3. Genetic interactions controlling DV patterning of the truncal nervous system in Drosophila and vertebrates.

Figure 3

Genetic interactions controlling DV patterning of the truncal nervous system in Drosophila and vertebrates. A) Schematic cross section through a Drosophila embryo at the blastodermal stage. Intensity of red colour indicates gradient of Decapentaplegic (more...)

The genetic mechanisms establishing and maintaining the sharp borders between the domains of columnar gene expression in the VNC have been explored in detail. The columnar genes interact in a hierarchical cascade of transcriptional repression (also known as “ventral dominance”19) according to which vnd represses ind (and msh) in the ventral column and ind represses msh in the intermediate column. Thus, Vnd determines the ventral border of the Ind domain and Ind the ventral border of the Msh domain. The ventral border of the Vnd domain is defined by the mesoderm-specific genes twist and snail (for a review see refs. 20, 21). It is less clear how their dorsal borders are established. msh expression seems to be dorsally confined by the repressive activity of graded levels of Dpp and vnd expression by the Dorsal gradient, which activates vnd.22 The dorsal border of ind expression may be formed by the limited activity of Epidermal growth factor receptor (Egfr) and Dorsal,21 but also by the activity of spatially localized repressors, which are yet unknown.23 Egfr activity in the ventral and intermediate column regulates the fate of NBs derived from these columns and is further necessary for the maintenance of vnd expression in the ventral column.24-26 Furthermore, positional information provided by Dpp/BMP signalling contributes to patterning the neuroectoderm by repressing columnar genes in a threshold-dependent fashion.27

Columnar genes encode key regulators of NB identity and each column thereby gives rise to a population of distinctly specified NBs. However, whereas vnd, ind and Egfr have also been shown to be crucial for the formation of NBs in their respective column, this role appears dispensable for msh (for a review see ref. 20).

A Comparison with DV Patterning of the Spinal Cord in Vertebrates

Vertebrate genes closely related to vnd (Nkx2.1, Nkx2.2), ind (Gsh1, Gsh2) and msh (Msx1, Msx2, Msx3) are engaged in DV patterning of the developing neural plate (Fig. 2) (for a review see refs. 3, 21). However, compared to Drosophila, the genetic interactions which establish their domains of expression are less clear since the analysis in vertebrates is hampered by the large number of extrinsic signalling molecules involved and the inherent complexity of the genetic network due to the existence of multiple family members. For example, the Msx gene family in mouse comprises three copies of an ancestral msh/Msx gene.28-30

Although the spatial expression of the columnar genes in the neural tube closely mirrors the situation in Drosophila, there are apparent differences regarding the signalling mechanisms that act upstream. The floorplate/notochord at ventral and the roofplate at dorsal midline position of the developing neural tube represent two signalling centres, which induce (noncell-autonomously) dorsal and ventral neural fates. Similar to the floorplate, the mesectodermal ventral midline in Drosophila (which is specified by single minded and Egfr) operates as a signalling centre and plays an important role in the determination of cell fate in the lateral CNS and later in axon pathfinding.31-33 However, in vertebrates, the signalling molecule secreted by the floor plate is Sonic hedgehog (Shh), a member of the hedgehog (hh) gene family. Graded Shh activates (or represses) the expression of various interacting homeobox genes (among which are the vnd homologs Nkx2.1 and Nkx2.2, as well as Nkx6.1) and specifies the fates of neural progenitors in the ventral neural tube (vp0-3, vpMN; Fig. 3B)34 (for a review see refs. 8, 35). This contrasts the situation in Drosophila, in which the VNC is patterned 1) by Dorsal and Egfr, which induce vnd and ind (see above)22 and 2) by the TGFα homologue Spitz, which is secreted by the ventral midline and leads to graded activation of Egfr in the neuroectoderm.36,37 Hh, on the other hand, is expressed in segmental stripes orthogonal to the midline and controls cell fate within the ventral midline,38 but does not induce ventral-specific patterning genes in the adjacent neuroectoderm.

Much less is known about patterning and specification of dorsal and intermediate neuroblasts which descend from the dorsal half of the neural tube. In mouse, all three members of the Msx gene family are expressed in dorsalmost neuroblasts. While patterns of Msx1 and Msx2 expression are largely overlapping in several nonneural tissues as well, Msx3 is exclusively restricted to the dorsal column of neural progenitors39 (for a review see ref. 30). Msx expression in the dorsal column is determined by molecules of the TGFβ family secreted from the roof plate, among which are the Dpp-related BMP2/4. BMP2/4 activate and seem to define both the dorsal and ventral border of Msx expression.40 This appeared to be in contrast to Drosophila, where Dpp represses msh and thus defines only the dorsal border of its expression.22 However, it has recently been reported that graded Dpp activity helps establish the msh/ind and the ind/vnd borders as well by repressing msh, ind and vnd in a threshold-dependent fashion and that BMPs act in a similar fashion in chick neural plate explants.27 Gsh1 and Gsh2 are expressed in an intermediate column in the neural tube. Both genes are necessary for fate specification of intermediate progenitors (in the progenitor domains dp3-5; Fig. 3B). Gsh2 is proposed to act downstream of BMP/TGFß signalling.41 In Drosophila normal level of ind expression critically depends on Egfr signalling. Although an Egfr homolog has been identified in zebrafish, it does not seem to have an instructive function in neural patterning of the spinal cord42 (for a review see ref. 21). A further difference is that the expression domain of Gsh2 partly overlaps with that of the Msx genes and that expression of Msx1 and Msx3 is unchanged in Gsh2 single or Gsh1/2 double mutants. This indicates that Gsh2 cannot repress Msx1/3, opposite to the Drosophila VNC, where ind clearly represses msh. On the other hand, in both the vertebrate spinal cord and the Drosophila VNC, Msx/msh does not repress Gsh/ind.18,41

Interestingly, it has been shown that mouse Gsh1 (and Nkx2.2) does not function in Drosophila VNC development, suggesting that functional domains have become distinct over time. In contrast, function of zebrafish Nkx6.1 and fly Nkx6 seems conserved since in both species overexpression of the respective ortholog leads to the induction of supernumerary motoneurons.43

Further factors involved in the specification of intermediate identities remain to be resolved, as for example signals involved in fate specification of “dp6” progenitors. Such signals may include retinoid acid, which is also necessary for proper development of the adjacent ventral neural progenitors (for a review see ref. 44). In the vertebrate neural tube, gaps have been observed between the expression domains of the columnar genes, raising the possibility that other genes might fill in these gaps.18 It has been suggested that, in addition to the columns of msh/Msx, ind/Gsh and vnd/Nkx2, the early neural tube includes at least a fourth DV column which expresses the developing brain homeobox2 (Dbx2) gene.41,45,46 The Dbx2 expression domain is positioned between the intermediate Gsh1/Gsh2 and ventral Nkx6.1 column and includes the “dp6” progenitors. Its ventral border is determined by repressive activity of Nkx6.1, but the factor controlling its dorsal border is unknown. However, the Drosophila Dbx homolog, H2.0, although expressed in subsets of NBs and progeny cells, does not seem to be involved in DV specification of NBs since it is not expressed in the truncal neuroectoderm.41

DV Patterning of the Brain in Drosophila

The Drosophila larval brain develops from the procephalic neuroectoderm (pNE) which gives rise to a bilaterally symmetrical array of about 100 embryonic NBs.47 Presumably all embryonic NBs become postembryonically reactivated to form the adult brain,48 whereas in the VNC postembryonic mitotic activity becomes restricted to segment-specific subpopulations of NBs. The pattern of embryonic brain NBs neither exhibits an ordered segmental assembly, nor morphologically distinct subdivisions into anteroposterior rows or dorsoventral columns, as is at least transiently the case in the VNC. Accordingly, the segmental composition of the brain is not obvious. The brain is subdivided, from posterior to anterior, into the tritocerebrum, deutocerebrum and protocerebrum (Fig. 1A-C). The embryonic trito- and deutocerebrum correspond to one neuromere each, deriving form the intercalary and antennal segment, respectively. There is evidence that the protocerebrum may consist of two neuromeres, a large one deriving from the ocular segment and a small remnant of the labral segment.49,50 Likewise, DV regionalisation of the early embryonic brain is not overt and the underlying patterning mechanisms are only rudimentarily understood. The columnar genes are expressed in distinct areas of the pNE and the developing brain. Although their expression is consistent with their role in DV patterning being principally conserved in the procephalon, there are also significant differences in their patterns of expression as compared to the trunk.

Expression of Columnar Genes in the Early Embryonic Brain

At the gastrula stage, vnd is expressed in the ventral pNE, covering the prospective ventral parts of the trito-, deuto- and protocerebrum. While Vnd in the trunk, is maintained within a continuous ventral neuroectodermal column during subsequent stages, vnd expression in the early brain is highly dynamic. It becomes progressively confined to three separate ventral domains at the posterior border of the trito-, deuto- and protocerebrum, encompassing different numbers of NBs and progeny cells (Fig. 4A).51,52 msh is expressed in the dorsal neuroectoderm of the intercalary and antennal segments which give rise to trito- and deutocerebral NBs. It is not expressed in the primordium of the protocerebrum. In the trunk, ind is expressed in a continuous column of intermediate neuroectoderm, whereas in the procephalic neuroectoderm it is found in three separate spots (in the intercalary, antennal and ocular segment). The intercalary and antennal ind spot are located at intermediate position between the dorsal Msh and ventral Vnd domain. Opposed to that, the ocular ind spot is spatially clearly separated from the ventral Vnd domain (and msh is not expressed). Due to the insulated expression of ind, the intercalary and antennal domains of msh and vnd expression share a common border at sites lacking an intervening ind domain.50

Figure 4. DV patterning of the embryonic brain in Drosophila and vertebrates.

Figure 4

DV patterning of the embryonic brain in Drosophila and vertebrates. A) Expression of the columnar genes msh, ind and vnd (see colour code) in neuroblasts of the tritocerebrum (T), deutocerebrum (D) and protocerebrum (P) at the embryonic stages 9 and 11. (more...)

Another conspicuous difference to the trunk (and to the TC and DC as well) is that a large amount of the protocerebral NBs (more than 50%) does not express any of the three columnar genes (Fig. 4A).50 Similarly, in the vertebrate spinal cord gaps have been detected between the domains of columnar gene expression.18 Thus, DV patterning of the protocerebral primordia of the brain anlagen requires factors additional to those encoded by the columnar genes. Candidate genes might include Egfr,24-26 the Sox genes SoxNeuro and Dicheate,53-55 the Nkx2.1 homologous gene scarecrow,56 the Nkx6 family related gene Nk6,43,57 or perhaps the Dbx homologous gene, H2.0.58 Most of these, except scarecrow and H2.0, are known to have a function in fate specification and/or formation of NBs in the trunk. Egfr, both Sox genes and Nk6 are expressed in the pNE before and during the phase of NB formation43,57 (J.Seibert and R.U., unpublished observations), however, their role in the formation/specification of brain NBs is yet unknown.

Segment-specific Regulation of Columnar Genes

Recent reports gave first insights into the interactions and function of columnar genes during DV patterning of the embryonic brain.51,52 Although principally the same DV patterning genes operate in large parts of the pNE, their regulation reveals segment-specific differences both among the brain segments and compared to the trunk (Fig. 4B).

For example, contrary to the trunk, in vnd mutant background derepression of ind within the ventral pNE does not occur in the antennal segment. Instead, ind expression is completely absent, indicating that, at least in this part of the pNE and brain, vnd is necessary for activation and/or maintenance of ind rather than for its repression (as in the trunk). This is supported by the finding that ectopic expression of vnd does not repress ind in the antennal segment. The ocular ind spot is often ventrally expanded in the absence of Vnd, which is reminiscent of the situation in the trunk. However, in the wildtype, the ocular ind spot does not adjoin the ventral domain of vnd expression. Hence, a ventral expansion of ocular ind in vnd mutants cannot be due to the lack of repression by Vnd and may be regulated noncell-autonomously.52

Moreover, in the absence of Vnd, expression of msh reveals segment-specific differences. Its expression is ectopically expanded into the ventral pNE of the intercalary and antennal segment, due to lack of repression by Vnd and Ind. This is not the case in the neuroectoderm of the protocerebrum and trunk. In the latter ind is derepressed instead of msh.

Taken together, expression and interactions of columnar genes (i.e., the cascade of transcriptional repression which establishes the ventral border of the msh and ind domain) appears to be conserved in the most posterior brain, the tritocerebrum. Although the expression of columnar genes is to some extent conserved in the deutocerebrum as well, their genetic interactions are more derived in the deuto- and protocerebrum.52 So far it is not settled how these segment-specific differences are regulated. It also remains to be clarified in how far other factors (e.g., those described above) genetically interfere with the columnar genes in the pNE and may establish the gene-specific extent of their expression both in the DV and AP axis.

Role of Columnar Genes in Formation of Brain NBs

In vnd mutants, ventral brain NBs are largely absent indicating that, similar to the situation in the trunk, vnd promotes formation of NBs. In the absence of Vnd, cell death is increased and acts at the level of both, neuroectodermal progenitors cells and NBs.52 It is not yet resolved if the reduction in ventral NBs is solely due to an increase in cell death or involves other factors known to be engaged in NB formation, such as proneural genes of the AS-complex (acheate, scute, lethal of scute [l′sc]; for a review see ref. 59). In the trunk, there is evidence that vnd interacts with proneural genes, but may also have additional function in promoting NB formation. Accordingly, in vnd mutant embryos, l′sc is still expressed in ventral proneural clusters, although the respective NBs will not form (e.g., NB5-2).13,60 In the pNE, genes of the AS-complex are expressed in large proneural domains and the acheate and l`sc domain seem to overlap with the domain of vnd expression, compatible with a genetic interaction.47,61 However, in vnd mutant embryos no substantial difference to the wildtype expression pattern of l′sc transcript is observed (R.U., unpublished observation), suggesting that, if vnd has proneural activity, it is rather independent of l′sc. Nevertheless, the expression of another proneural gene, atonal (in the pNE normally expressed in proneural clusters and developing sensory precursors of the hypopharyngeal-/latero-hypopharyngeal organ), is often missing indicating its dependence on Vnd.52 Thus far it is unclear if msh, ind and Egfr exert a similar function in brain NB formation. Whereas Egfr mutant embryos exhibit strong defects in the number and pattern of brain NBs, they appear rather unaffected in msh mutants ( J.Seibert and R.U., unpublished observation), indicating that at least msh does not play a role in brain NB formation. Egfr signalling has also been shown to be necessary for the proper development of medial brain structures deriving from the head midline, which behaves like the mesectoderm in the trunk.62 Placode-like groups of cells from the head midline invaginate and contribute subpopulations of cells to the brain.61 Loss of Egfr signalling results in severe reduction or absence of the respective head midline derivatives.

Role of vnd in Specification of Brain NBs

In the trunk, evidence has been provided, that the set of genes expressed within a proneural cluster specifies the individual identity of the NB it gives rise to. Such a combinatorial code, which is unique for each NB, is provided mainly by the superimposition of the acitivity of DV patterning genes and segment polarity genes (AP axis) and a number of other factors (for a review see refs. 9, 20, 63). Most of these genes are also expressed in specific procephalic neuroectodermal domains before NBs delaminate, implying that these genes might be required for specification of individual brain NBs as well.64 Analysis of an array of such NB identity genes in vnd loss- and gain-of function backgrounds indicates that, similar to the situation in the trunk, vnd influences their expression already in the pNE, before the formation of NBs.52

In vnd loss-of-function background, dorsal-specific gene expression is derepressed in the ventral pNE and descending NBs and conversely, ventral-specific gene expression is lost, suggesting a ventral-to-dorsal transformation of the mutant ventral pNE and residual ventral NBs. This indicates that vnd normally activates genes specific for the ventral pNE and represses genes specific for dorsal pNE and is required for fate specification of ventral brain NBs. This is further supported by the production of ectopic glial cells derived from transfated ventral NBs in the trito- and deutocerebrum, which normally is a specific trait of dorsal brain NBs. Later in embryogenesis a severe loss of neural tissue associated with increased apoptotic activity has been observed in the tritocerebrum, presumably as a consequence of identity changes imposed on vnd deficient NB lineages.51

Upon vnd overexpression, there is a wide-ranging loss of dorsal-specific gene activity in the dorsal pNE and NBs, but a largely unaffected ventral-specific gene activity in ventral parts. Moreover, there is evidence for a partial dorsal-to-ventral transformation of dorsal parts of the pNE and corresponding NBs, which indicates that Vnd is not only necessary but to some extent also sufficient to induce ventral traits.

A Comparison with DV Regionalization of the Vertebrate Telencephalon

The telencephalon derives from paired evaginations of the anterior forebrain that constitute the most complex structures of the vertebrate CNS. Progress has been made in understanding the early regional patterning of the telencephalon, although the present knowledge about its DV regionalization is still rudimentary. The telencephalon can be subdivided into a dorsal or pallial and a ventral or subpallial territory and the subpallium further into the lateral ganglionic eminence (LGE) and a ventralmost part, the medial ganglionic eminence (MGE) (Fig. 1). The pallium gives rise to the cortex, the subpallium to the basal ganglia. The future telencephalic territories can be defined early in development by the expression of Nkx2.1 in the ventral MGE and Gsh1, Gsh2 in the intermediate LGE, resembling the expression of vnd and ind in the anlagen of the Drosophila brain. Pax6, the homolog of Drosophila eyeless (ey), is expressed in the dorsal telencephalon (Fig. 4C). Pax6 is involved in the specification of pallial identity (for a review see refs. 66, 67) instead of Msx genes which are not expressed in the telencephalon. Interestingly, Drosophila ey is likewise preferentially expressed in dorsal/intermediate NBs of the protocerebrum, which lack msh expression,64 suggesting that ey may to some extent play the role of msh in the anterior brain. In the telencephalon, Nkx2.1, Gsh2 and Pax6 are complementary expressed, provide some of the earliest markers for the respective territories and are key regulators for their normal development (for a review see ref. 67).

Genetic Interactions of Columnar Genes

Although a conserved set of homeobox genes is expressed at corresponding DV positions in the brains of arthropods and vertebrates, there are differences in their genetic interactions. In the telencephalon Gsh2 and Pax6 cross-repress each other, which results in the formation of a sharp border between the dorsal and intermediate domains (Fig. 4C, D). Accordingly, in Pax6 mutant mice there is evidence for a dorsal-to-ventral transformation of dorsal (pallial) structures, which is opposite to the phenotype in Gsh2 mutants.68-70 This behaviour is specific to the telencephalon and not observed in the spinal cord. Similarly, in the Drosophila protocerebrum and deutocerebrum, ey and ind are largely expressed in complementary subsets of NBs.64 However, ey expression does not seem to depend on Ind, since it does not expand ventrally in ind mutants (R.U., unpublished observations), as opposed to Pax6 in the telencephalon of Gsh2 mutants.69 In the tritocerebrum, opposite to the anterior brain, ey is coexpressed with ind,64 resembling the situation in the vertebrate spinal cord, in which the domains of Pax6 and Gsh2 overlap.41,67 It is worth noting, that Drosophila has a second Pax6 gene, twin of eyeless (toy), which is largely expressed in the protocerebrum. However, since ind is coexpressed with toy in the protocerebrum,64 it is unlikely that ind and toy (instead of ey) genetically behave in a way similar to Pax6 and Gsh2 in the telencephalon.

Among the columnar genes, particularly the family of Nkx/vnd genes seems to be well conserved in terms of expression and function. In mice carrying a deletion of Nkx2.1, a substantial loss of ventral, especially of forebrain structures has been observed. The residual ventral (subpallial) structures become transfated into dorsal striatal structures.71 An interesting correlation between the regulation of columnar genes in the vertebrate telencephalon and Drosophila deuto- and protocerebrum is that Nkx2.1 and vnd do not repress the expression of Gsh and ind, respectively. Accordingly, in Nkx2.1 knockout mouse, as well as in Drosophila vnd mutants, the expression of Gsh2/ind in these brain regions is not ventrally expanded,51,71 contrary to findings made in the truncal CNS (for a review see ref. 21). Instead of intermediate Gsh/ind, dorsal-specific marker genes are derepressed in ventralmost areas of the early brain; among these are Pax6, in the vertebrate telencephalon and ey (to a minor extent) and especially msh in the Drosophila deuto-and tritocerebrum. Together, this suggests that in Nkx2.1/vnd mutant background, residual ventral brain territories undergo a ventral-to-dorsal rather than a ventral-to-intermediate transformation, the latter being observed in the truncal CNS of both species.13,73,74

Genetic Factors Upstream of the Columnar Genes

Several extrinsic signalling molecules are involved in DV patterning of the telencephalon, among which are BMPs, Wnts, Gli, FGFs, Nodal, retinoic acid and the central player Shh (for a review see refs. 44, 67, 75). The mechanisms by which Shh induces DV fate might differ between spinal cord and brain. Whereas in the spinal cord, the fates induced by Shh are concentration-dependent, Shh-induced fates in the telencephalon depend on timing rather than concentration (for a review see ref. 67). In the telencephalon, the source of secreted Shh is (among others) the prechordal plate, a mesodermal derivative. Remarkably, the Drosophila homolog, Hh, secreted from the head mesoderm and foregut, acts on brain morphogenesis by regulating size and apoptosis. hh, expressed in the foregut, appears to mediate these effects via the Hh receptor patched (expressed in brain cells surrounding the foregut). These similarities may indicate an ancient mechanism of brain patterning via induction.76 In how far other extrinsic signalling molecules are involved in DV patterning of the Drosophila brain remains to be shown.

Conclusions

A conserved set of columnar genes (msh/Msx, ind/Gsh, vnd/Nkx) is involved in DV regionalization of the brain and truncal CNS in vertebrates and arthropods (Drosophila). The expression of columnar genes in the brain differs from the truncal CNS in both animal phyla. Remarkably, the brain-specific expression of columnar genes exibits striking parallels between Drosophila and mouse in that the anterior borders of their domains are corresponding: Expression of vnd/Nkx2 extends most rostrally, followed by ind/Gsh1 and finally by msh/Msx3 (for a review see ref. 77). Thus, the expression of columnar genes in the brain is, to some extent, evolutionarily conserved, not only along the DV axis but also along the AP axis.

Moreover, brain-specific interactions among columnar genes bear some similarities between vertebrates and Drosophila. For example, Gsh/ind are not repressed by Nkx2.1/vnd and expression of dorsal factors, instead of intermediate, is expanded into ventral domains in vnd/Nkx2 mutant brains. This suggests that at least part of the genetic mechanisms governing DV fate in the brain have been conserved as well. Differences may become more obvious at the level of upstream regulating factors. However, in vertebrates, as well as in Drosophila, the genetic basis underlying DV regionalization of the brain is far from being understood. The Drosophila brain, due to its comparatively small size, allowing resolution at the level of individually identified cells and to the powerful genetic and experimental tools available, provides a useful model system to study these mechanisms in detail. This will facilitate the clarification of the processes underlying DV regionalization in the brain of other organisms, including vertebrates.

Acknowledgements

We are grateful to Ana Rogulja-Ortmann for comments on the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft and the EC.

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