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Important Role of Shh Controlling Gli3 Functions During the Dorsal-Ventral Patterning of the Telencephalon

* and .

* Corresponding Author: Molecular Neuropathology Group, Brain Science Institute, RIKEN, Hirosawa, Wako, Saitama 351-0198, Japan. Email: jun@brain.riken.go.jp

The dorsal-ventral patterning of the telencephalon is a crucial for the normal brain function, because it determines the proportion of two different types of basic neurons, glutamatergic excitatory neurons and GABAergic inhibitory neurons. The secreted protein sonic hedgehog (Shh) is required for the ventral cell specification, whereas zinc finger transcription factor Gli3 seems to be important for the dorsal cell type specification. Recent studies suggest that how both Gli3 and Shh control the normal proportion of dorsal and ventral cell types to generate appropriate tissue size and shape during brain development. These observations may offer a new aspect to our understanding of activity gradient of Shh signal during brain development.

Introduction

Embryogenesis involves a complex coordination of cell fate specification, proliferation and differentiation that are determined by the actions of a legion of genes. The sonic hedgehog (Shh) signaling cascade is important in many developmental processes of the central nervous system, and dysfunctions in this pathway can lead to birth defects and brain tumor.1-7 Although the roles of the individual genes of Shh signaling cascade in each of these developmental processes have started to be defined, how these gene functions combine to translate the dynamic assembly of cells into tissues remains unresolved. Recent genetic studies using combined mutant mice have provided new insights into how several genes control the normal proportion of different cell types to generate appropriate tissue size and shape. Here, we review the role of Shh and Gli3 during dorsal-ventral patterning of the mouse telencephalon revealed by the analyses using not only Gli3 and Shh single mutants and also Gli3/Shh double mutant mice.

Shh Signaling and Dorsal-Ventral Patterning of the Telencephalon

Sonic hedgehog (Shh) is a secreted protein that controls the patterning and proliferation of many tissues in developing human and mouse embryos. Many of the components that mediate the Shh signaling in these embryos were first discovered as genes homologous to those affecting early embryonic development in Drosophila. In Drosophila, hedgehog (Hh) is a secreted protein that is required for the pattern formation during many process of fly development. Two transmembrane proteins, patched (Ptc) and smoothened (Smo), are involved in the reception of the Hh signals8,9 and a transcription factor, cubitus interrupts (Ci) is the ultimate transducer inside target cells of the signaling.10 In the absence of Hh, Ptc inhibits Smo function, allowing proteolytic cleavage of Ci which then suppresses the transcription of target genes.11 However, when Hh binds to Ptc, the repressive action of Ptc on Smo is blocked, Ci proteolysis is inhibited, and Ci is converted into a transcriptional activator. Several features of this Hh signal transduction are evolutionarily conserved in vertebrates, and when this pathway is impaired birth defects and tumorigenesis result. Shh is encoded by one of three mammalian orthologous genes to Hh, desert hedgehog, Indian hedgehog and sonic hedgehog. Mice and humans have at least three Ci orthologuos genes (Gli1, Gli2, and Gli3) encode transcription factors mediating Shh signaling.12-17 Of these, Gli2 and Gli3 can be proteolytically processed and seem to have transcriptional activator and suppressor functions18,19 (fig. 1). Mouse Gli genes are introduced in the fly wing disc to examine whether the processing of mouse Glis can be regulated by Drosophila Hh signaling.18 Gli1 and Gli2 can function as activators of Hh signaling in the fly disc. Gli2 and Gli3 are processed in the fly wing disc, but the processing of Gli2 is observed in even within the posterior compartment expressing Hh signaling, suggesting that it is not regulated by Hh signaling. On the other hand, the proteolytic cleavage of Gli3 is regulated by Hh signaling in a similar manner to how Ci is regulated by Hh in Drosophila.18 Gli1 seems to have only an activator function18 (fig. 1). Also in the developing limb buds in mouse and chick embryos, proteolytic cleavage of Gli3 is observed and its distribution is appears to be regulated by Shh from posterior region of limb named ZPA (zone of polarizing activity).19 Thus, not only in Drosophila also in mouse and chick, proteolytic processed Gli3 is appears to be a specific antagonist against Shh signaling.

Figure 1. Schematic diagram of Ci/Gli family protein structure.

Figure 1

Schematic diagram of Ci/Gli family protein structure. All members have the zinc finger domain (ZFD) and the activator domain in the C-termini (gray). Ci/Gli except for Gli1 have the repressor domain in the N-termini (black) and act as repressor by processing (more...)

The dorsal-ventral patterning of telencephalon determines the proportion of two different types of basic neurons, glutamatergic excitatory neurons and GABAergic inhibitory neurons, which are necessary for the normal telencephalon function. Fibroblast growth factor 8 (Fgf8) is essential regulator for the dorsal-ventral patterning of the telencephalon. At the head fold stage, around 8.0 dpc, the presumptive forebrain is determined and the cells in the anterior-most aspect start expressing Fgf8. The Fgf8 expressing in anterior neural ridge are important for outgrowth of the telencephalon territory in the forebrain region (fig. 2A,B). Depending on the effect of the Fgf8, the surrounding neural plate grows rapidly and forms a pair of brain vesicles that becomes the presumptive telencephalon20,21 (fig. 2C-G). The dorsal part of telencephalon develops into the neocortex and hippocampus, mainly generating excitatory glutamatergic projection neurons. The ventral telencephalon develops into lateral and medial ganglionic eminences (fig. 2H-J). The majority of the neurons generated in the ganglionic eminences are inhibitory GABAergic interneuron, which tangentially migrate to the neocortex and make a circuit with excitatory projection neurons. Thus, this dorsal-ventral patterning is important to maintain the proper balance between two different types of basic excitatory and inhibitory neurons.

Figure 2. Distribution of Fgf8 expression during the telencephalon development.

Figure 2

Distribution of Fgf8 expression during the telencephalon development. Scanning electron micrographs of embryonic telencephalon isolated from different stages during embryogenesis. Green area indicates the presumptive telencephalon in the frontal (A, C, (more...)

Shh and Gli3 functions are required for this dorsal-ventral patterning of the telencephalon. Shh is expressed in the ventral midline and Gli3 is in the dorsal telencephalon22 (fig. 3A,B,D). Shh is thought to be essential for directing the formation of the ventral telencephalon, because the medial and lateral ganglionic eminences are severely affected and single forebrain vesicle is developed with missing midline structure in Shh-/- mouse embryos23 (fig. 4B). However, the severe brain malformations observed in Shh-/- mutant embryos are restored in Gli3/Shh double mutant embryos22,24,25 (fig. 4C). This finding suggests that the phenotype in Shh-/- single mutant mice includes the defects caused secondary. Moreover, the restored phenotype also suggests that Gli3 function is involved in the secondary defects observed in Shh-/- mutant mice (fig. 4B). The important question is how Gli3 functions with Shh to regulate the normal proportion of different cell types to generate appropriate tissue size and shape during the telencephalon development.

Figure 3. Distribution of Shh, Gli3 and Fgf8 mRNA in the telencephalon of wild type at 11.

Figure 3

Distribution of Shh, Gli3 and Fgf8 mRNA in the telencephalon of wild type at 11.5 dpc (A, B, C) and schematic diagram of genes expression in the telencephalon (D). Frontal views of the telencephalon after whole mount in situ hybridization are shown in (more...)

Figure 4. Dorsal-ventral patterning defects in Shh and Gli3 single mutants can be explained by the disrupted balance between Shh and Gli3 functions.

Figure 4

Dorsal-ventral patterning defects in Shh and Gli3 single mutants can be explained by the disrupted balance between Shh and Gli3 functions. A-D) Effects of Shh and Gli3 loss-of-function mutations on the dorsal-ventral patterning of the telencephalon. Summarizing (more...)

Gli3 As an Activator of Dorsal Cell Types

What is the role of Gli3 protein in the developing brain? Gli3 seems to be required for the development of dorsal cell types and essential for the suppression of ventral specification in the telencephalon based on its expression pattern and the phenotype observed in Gli3-/- single mutant mice22,26,27 (fig. 3, fig. 4DD). During telencephalon development, Gli3 is expressed in the dorsal edge of the neural plate in 8.0 dpc embryos and restricted to the dorsal telencephalon (fig. 3C,D). The mouse Gli3 XtJ/XtJ (-/-) mutant is a model for human Greig cephalopolysyndactyly syndrome because it shows several features of the disease described by Johnson.28 In Gli3-/- mutant embryos, the number of the cells in the dorsal telencephalon, marked by Emx1/2 expression (fig. 3D), is obviously reduced, resulting in a severe reduction of the cortex, olfactory bulb and hippocampus26,27 (fig. 4D). On the other hand, ventral cell types marked by Nkx2.1 and Dlx2 expression are expanded22,25,29 (fig.3D, fig. 4D). Based on these observations, it appears that Gli3 is required for dorsal cell type specification. While the dorsal telencephalon is greatly reduced, the medial and lateral ganglionic eminences in the ventral telencephalon are clearly expanded in Gli3-/- mutant embryos22,29 (fig. 4D). Thus, Gli3 may have at least two major functions in the developing telencephalon: promotion of dorsal cell types and suppression of ventral cell types (fig. 4E).

This malformation observed in Gli3 mutant brain may be explained by the up-regulation of Fgf8 during telencephalon development, because Fgf8 can promotes the development of the ventral cell fates and suppresses dorsal cell specification22,26,27,30 (fig. 3C, fig. 4D). The up-regulation of Fgf8 is observed in the neural tube of Gli3-/- embryos from 8.5 dpc, and it becomes more obvious at later stages22 (fig. 4D). The timing of brain malformation correlates with Fgf8 up-regulation, suggesting that the up-regulation induces the growth retardation of dorsal telencephalon and also promotes the development of ventral telencephalon (fig. 4E). Thus, Gli3 may promote the proliferation and differentiation of the dorsal cells by suppression of Fgf8 expression because Fgf8 participates in the inhibition of the dorsal cell development.

On the other hand, it is also highly possible that reduced bone morphogenetic proteins (Bmps) and Wnts genes expression observed in Gli3-/- mutant mice is involved in the abnormal dorsal telencephalon development. Bmps and Wnt proteins are secreted proteins normally expressed in most dorsal cells of the telencephalon and diencephalon, and they are known to be necessary for the dorsal cell type specification in the brain31-33 (fig. 3D). Because Bmps and Wnts genes expression are down-regulated in Gli3-/- mutant mice, it appears that Gli3 is required for the activation of these genes expression in the dorsal telencephalon and diencephalon26,27,32 (fig. 4D). Gli3 may be required for the promotion of dorsal telencephalon development via the activation of Bmps and Wnts genes expression (fig. 4E).

Gli3 As a Suppressor of Ventral Cell Type

Gli3 may function as a suppressor of ventral specification, because the number of ventral cells expressing Nkx2.1 and Dlx2 is increased in Gli3-/- mutant embryos22,25,27,29 (fig. 4D). The suppressor function of Gli3 in the spinal cord is clearly shown by Persson et al (2002)34 and Meyers and Rolink (2003).35 In Gli3-/- mutant embryos, the number of V0 and V1 interneuron progenitors expressing Nkx6.2 is increased in the intermediate zone of the spinal cord. On the other hand, dorsal cell types, motor neuron, V3 interneuron progenitors and floor plate are not affected, suggesting that Gli3 suppresses the generation of V0 and V1 interneuron progenitors during normal spinal cord development. The next question is whether the specification of these interneuron progenitors are suppressed by an intact or a proteolytically processed Gli3, because Shh may block the proteolytic cleavage of Gli3 in the intermediate zone of the spinal cord. To identify which form of Gli3 is responsible for the suppression of V0 and V1 interneuron progenitors, the mutant mice with targeted mutation of Gli3 have been generated.34,36 In these mutant mice only processed form of Gli3, which is missing C-terminal activator domain by premature termination of translation of Gli3 C-terminal of the zinc finger region, is expressed.36 Interestingly, their spinal cord displays normal dorsal-ventral patterning, clearly indicating that the processed form of Gli3 is enough to suppress and maintain the proper amount of V0 and V1 interneuron progenitors during the normal spinal cord development.34

The artificial processed Gli3 is also ectopically introduced into the ventral side of the chick spinal cord to examine the effect on other ventral cell types.34,35 Consistent with the finding in the targeted mutation of Gli3, the ectopic expression of the processed form of Gli3 can block the generation of V0 and V1 progenitors.34,35 Moreover, the processed form of Gli3 can also block the development of motor neuron, V3 interneuron and oligodendrocyte progenitors in the cell-autonomous manner. However, Shh expression in the floor plate is not affected. Based on these observations, the proteolytic cleavage appears to make Gli3 as a suppressor against not only V0 and V1 interneuron progenitors also against other ventral cell types. The suppressor function may not be required for the regulation of V2, V3 interneuron and motor neuron progenitors during normal development, because their development is not affected in Gli3-/- mutant spinal cord.34 However, in the telencephalon of Gli3-/- mutant mice, the expression of Fgf8, Dlx2 and Nkx2.1 are all increased in the intermediate zone and ventral region, strongly suggesting that the processed form of Gli3 is required for maintenance of proper amount of these ventral cell types during normal telencephalon development.22,25,26,27,29

Importance of the Balance Between Gli3 and Shh

Suppressor function of Gli3 against the ventral progenitors may be responsible for the absent of these progenitors in Shh-/- single mutant mice, which has been strongly suggested by the restored these cells in Gli3-/-;Shh-/- double mutant mice.24 Litingtung and Chiang (2000) showed that V2 inter neurons and motor neurons were restored in the spinal cord of Gli3-/-;Shh-/- double mutants.24 This finding strongly suggests that the absence of motor neuron and V2 interneuron progenitors in Shh-/- single mutant mice is caused by suppression of their specification by Gli3. Similar suppressor effect of Gli3 has also been revealed in the brain, as there is a severe lack of midline structure and expansion of dorsal cells in the brain of Shh-/- single mutants that is dramatically restored in Gli3-/-;Shh-/- double mutants22,25 (fig. 4B,C). The ventral-most aspect marker Nkx2.1 in the medial ganglionic eminence is restored in the double mutant telencephalon.25 These findings suggest that Shh signaling is not directly required for the specification of some ventral cell types, such as the cells in medial and lateral ganglionic eminences. Shh may be indirectly required for the ventral cell types to block the Gli3 suppressor function in the ventral telencephalon.

Activity gradient of Shh may regulate the amount of proteolytically processed Gli3 protein in the ventral region. The studies using artificial processed form of Gli3 showed that ectopic expression of proteolytically processed form of Gli3 can block the generation of interneuron and motor neuron progenitors in the spinal cord.34,35 It has been known that Hh regulates the processing of Gli3 in a similar manner to how Ci is regulated by Hh in Drosophila.18 Based on these observations, the amount of proteolytically processed Gli3 proteins may be less in the ventral region of the spinal cord and brain by activity gradient of Shh. Intriguingly, not only blocking the development of ventral cell types, the processed form of Gli3 can induce a ventral-to-dorsal shift in progenitor cell identity in the cell autonomous manner, suggesting that the amount of proteolytically processed form of Gli3 is involved in the direction of the dorsal-ventral patterning.34,35

Future Perspectives

These studies suggest a combined action of Shh and Gli3 function is fundamental in telencephalon development (fig. 4E). There appears to be two functions of Gli3 as an activator of dorsal cell types and as a suppressor of ventral specification, that seem to be related to the promotion of Bmps/Wnts expression and suppression of Fgf8 expression (fig. 4E). Gli3 may be involved in specific aspects of each of these processes. Although the studies in mutant phenotypes suggest the dual functions, it has yet to be confirmed directly. It is possible that the promotion of differentiation into dorsal cell types itself inhibits the differentiation into ventral cell types, and vice versa.

Gli3 function seems to be essential for dorsal cell specification, because the reduction of dorsal cells observed in the Gli3-/- telencephalon is not restored in the Gli3-/-;Shh-/- double mutants22 (fig. 4C,D). The regulation of Bmps/Wnts expression by Gli3 appears to be essential in determining dorsal cell types. Importantly, in the embryonic neuronal progenitors isolated from dorsal telencephalon, the inhibition of Bmp signaling was reported to be sufficient in determining ventral cell types shown by using cell culture system.37 Blocking Bmp signaling in the neuronal progenitors isolated from embryonic dorsal telencephalon with a dominant-negative Bmp receptor Ib can induce differentiation into inhibitory interneuron, even if Shh signaling is also blocked by cyclopamine, an inhibitor of Smoothened protein.37 Thus, for the dorsal progenitor cells, inhibition of Bmp signaling is necessary and sufficient for the induction of dorsal-to-ventral shift in progenitor cells identity. Based on the mutant phenotype analyses and ectopic expression experiments, we already know that Gli3 is required for the activation of Bmps genes expression27 and processed form of Gli3 can induce a ventral-to-dorsal shift in the progenitor cell identity.34,35 These findings suggest that Shh is required for inhibition of dorsal cell specification by inhibiting Bmp signaling via the conversion of Gli3 suppressor form into an activator form only in the ventral region. Spatial and temporal distribution of Gli3 suppressor form regulated by activity gradient of Shh may control the normal proportion between dorsal and ventral territories.

Because most of the results introduced here are based on analyses of tissue from mutant animals, many unanswered questions about the functions of Gli3 and Shh proteins remain. Confirmation of the cellular functions of Gli3 is essential to extend these results to the molecular level.

These observations indicate that the proper balance between Shh and Gli3 functions is important for the normal dorsal-ventral patterning of neural tube and brain. As Shh and Gli3 are inhibiting each other, when one is missing severe malformation results as remaining expands to the other side. Recent findings using double mutant studies revealed that both Shh and Gli3 regulate a set of specific cell types during neural tube and brain development compared to those we expected. Moreover, when both are absent many cell types located in the intermediate zone of the brain and neural tube develop normally, indicating that Shh and Gli3 can only modulate the dorsal-ventral patterning established by other signaling pathway. Bmp/Wnt signaling and their antagonists are essential for neural plate development and its specification before the expression of Shh in the neural plate cells has been established.38,39 It is likely that other signaling pathways participate in dorsal-ventral patterning in the telencephalon, but their precise roles and whether they act in concert or in parallel with Shh signaling requires further investigation.

Acknowledgements

We thank Drs. Adrian Moore and Bonnie Lee Madeleine for helpful discussion and critical reading of the manuscript.

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