Hedgehog–GLI signaling and the growth of the brain View Full Text


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Article Info

DATE

2002-01-01

AUTHORS

Ariel Ruiz i Altaba, Verónica Palma, Nadia Dahmane

ABSTRACT

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. More... »

PAGES

24-33

References to SciGraph publications

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/11823802


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