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  • Review Article
  • Published:

Hedgehog–GLI signaling and the growth of the brain

Key Points

  • What drives the growth of the brain during development and how mammalian brains have evolved to reach their current level of complexity remains largely unknown. Many secreted factors, the function of which we are only beginning to understand, affect brain development. In this context, the function of the Sonic hedgehog (SHH)–Gli signalling pathway has received significant experimental attention.

  • SHH is a member of the hedgehog family of secreted glycoproteins. SHH acts through the Patched 1/Smoothened receptor complex. Cells that respond to SHH upregulate the transcription of the zinc-finger transcription factor Gli1. There are three Gli proteins — Gli1–3 — which participate in the mediation, interpretation of or response to the SHH signal in a context-dependent manner.

  • In the embryonic brain, SHH is first expressed ventrally, and is involved in the development of ventral hindbrain, midbrain and forebrain. After this early period of expression, SHH starts to appear in other brain areas, including cerebellar Purkinje neurons and the neocortex.

  • SHH induces purified granule neuron cerebellar precursors to proliferate, and inhibition of SHH signalling in vitro results in a decrease in proliferation. In vivo, inhibition of SHH signalling results in a decrease of proliferation in the external germinal layer, and in disorganization of the Purkinje layer.

  • The expression of SHH in the neocortex is paralleled by the expression of Gli1 in the ventricular zone. SHH produced by differentiated cells in the cortical plate might affect precursor cells near the ventricle. Moreover, SHH increases the proliferation of neocortical precursors, whereas its inhibition leads to a downregulation of proliferation. Loss of Gli3 results in cortical defects, indicating an action of Gli proteins in cortical development.

  • Many questions in this field remain unanswered. Do the SHH–Gli-mediated mechanisms that control growth also determine the foliated shape of the cerebellum and the pattern of cerebral sulci? Is there a role for SHH in the adult brain?

  • More immediate questions on the role of SHH–Gli signalling also need to be addressed. What is the role of each Gli protein? Their combinatorial, context-specific effects have made it difficult to address this issue. How does the SHH–Gli pathway affect the cell cycle? SHH upregulates the expression of cyclins, but we still lack an integrated view of its role in controlling the cell cycle. How does SHH reach its distant targets? Does it merely diffuse, is it actively transported or does its movement involve cytonemes?

  • Another important issue that remains to be resolved is related to the interaction of the SHH–Gli signalling pathway with other factors. So far we have a few clues as to its interaction with bone morphogenetic proteins, fibroblast growth factors and Wnt proteins, but we still lack an integrated picture of their actions, and we need to explore the interplay between SHH–Glis and other molecules, such as insulin-like growth factors and neuregulins.

Abstract

The development of the vertebrate brain involves the creation of many cell types in precise locations and at precise times, followed by the formation of functional connections. To generate its cells in the correct numbers, the brain has to produce many precursors during a limited period. How this is achieved remains unclear, although several cytokines have been implicated in the proliferation of neural precursors. Understanding this process will provide profound insights, not only into the formation of the mammalian brain during ontogeny, but also into brain evolution. Here we review the role of the Sonic hedgehog–Gli pathway in brain development. Specifically, we discuss the role of this pathway in the cerebellar and cerebral cortices, and address the implications of these findings for morphological plasticity. We also highlight future directions of research that could help to clarify the mechanisms and consequences of Sonic hedgehog signalling in the brain.

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Figure 1: SHH-triggered intracellular events leading to Gli function.
Figure 2: Layer-specific expression of SHH in dorsal regions.
Figure 3: Morphology and development of dorsal brain structures.
Figure 4: Role of Sonic hedgehog in cerebellar growth.
Figure 5: Interactions between secreted signalling molecules and Gli function.
Figure 6: SHH signalling and the cell cycle.

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Acknowledgements

We are grateful to J. L. Mullor, P. Sánchez and Y. Gitton for comments. V.P. is a Latin-American Pew Fellow. Work in A.R.A.'s laboratory is supported by grants from the March of Dimes, the National Cancer Institute and National Institute for Neurological Disorders and Stroke. The laboratory of N.D. is funded by grants from the Centre National de la Recherche Scientifique, La Fondation pour la Recherche Médicale and L'Association pour la Recherche sur le Cancer. Due to space limitations, only a proportion of relevant references could be cited here.

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Correspondence to Ariel Ruiz i Altaba.

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DATABASES

FlyBase

Ci

disp

dpp

ptc

ttv

LocusLink

BF-1

BMP

brachyury

β-catenin

Cdk

CREB

cyclin B

cyclin D2

E2F

EGF

Emx

FGF

Gas1

Gli1

Gli2

Gli3

Hip

IGF

nestin

neuregulin

Notch

PACAP

PDGF

Ptc1

Rab23

Rb

SHH

Smad

Smo

Su(fu)

vitronectin

Wnt

FURTHER INFORMATION

cerebral cortex development

neuronal subtype identity regulation

Glossary

FIBROBLAST GROWTH FACTORS

Multifunctional factors that are involved in embryonic development. More than 20 FGFs and 4 FGF receptors have been described. Their coordinated activity controls cell proliferation, migration, survival and differentiation. FGFs regulate growth and morphogenesis by an early action on regional patterning, and a later effect on the growth of progenitor cells of the forebrain.

WNT PROTEINS

A family of highly conserved secreted signalling molecules that regulate cell–cell interactions during embryogenesis. Wnt proteins bind on the cell surface to receptors of the Frizzled family.

HEDGEHOG FAMILY

A group of paracrine signalling molecules with multiple roles during development. It includes Hedgehog, which specifies the segmental polarity of the blastoderm and cell fate in imaginal discs of Drosophila; Sonic hedgehog, which participates in multiple aspects of neural development in vertebrates; Indian hedgehog, which participates in endoderm differentiation and bone growth; and Desert hedgehog, which is involved in spermatogenesis.

BONE MORPHOGENETIC PROTEINS

Multifunctional secreted proteins of the transforming growth factor-β superfamily. In the early embryo, they participate in dorsoventral patterning.

CYCLINS

A family of proteins, the levels of which fluctuate throughout the cell cycle. By activating cyclin-dependent kinases, they help to regulate several stages of cell division.

SMADS

A family of transcription factors that mediate transforming growth factor-β signals. The term SMAD is derived from the founding members of this family, the Drosophila protein Mad (Mothers against Decapentaplegic) and the Caenorhabditis elegans protein SMA (small body size).

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Ruiz i Altaba, A., Palma, V. & Dahmane, N. Hedgehog–GLI signaling and the growth of the brain. Nat Rev Neurosci 3, 24–33 (2002). https://doi.org/10.1038/nrn704

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