Review
Sonic hedgehog in the nervous system: functions, modifications and mechanisms

https://doi.org/10.1016/S0959-4388(02)00290-8Get rights and content

Abstract

Signaling by Sonic hedgehog (Shh) controls important developmental processes, including dorsoventral neural tube patterning, neural stem cell proliferation, and neuronal and glial cell survival. Shh signaling involves lipid modifications to Shh itself, as well as changes in protein subcellular localization. Recent advances have revealed the importance of palmitoylation and acylation of Shh on its potency and migration capacity. Subsequent trafficking and organelle sorting in the Shh signaling pathway have been observed; these observations offer a new dimension to our understanding of downstream signal transduction events.

Introduction

Sonic hedgehog (Shh), a member of the Hedgehog (Hh) family of secreted signaling proteins, carries out diverse functions during vertebrate development. Humans or mice lacking Shh develop holoprosencephaly and cyclopia due to a failure of separation of the lobes of the forebrain [1], [2]. In the neural tube, Shh, secreted from the notochord and later from the floorplate, directs cell fate choices in a dose-dependent manner. Recent work from many groups has greatly expanded the depth and breadth of our understanding of Shh signaling in the nervous system. Here, we first review the advances that further characterize Shh's many roles in neural development, then we turn to a discussion of new insights gleaned from studies of the Shh and Hh signal transduction mechanisms.

The graded activity of Shh in patterning the neural tube was elegantly demonstrated using various concentrations of purified Shh to elicit dose-dependent gene activity in neural tube explants [3]. Shh organizes the developing neural tube by establishing distinct regions of homeodomain transcription factor production along the dorsoventral axis [4•]. These transcription factors, including Nkx, Pax, and Dbx family members, specify neuronal identity (reviewed in [5], [6]; Fig. 1). By ectopically activating Shh signaling in medial and dorsal cells of the neural tube, two groups [7], [8] showed that Shh signaling acts directly on target cells, not through other secreted mediating factors, to specify neural cell fates. Different concentrations of Shh thus cause cells to choose appropriately among many potential cell fates.

Shh also plays important patterning roles elsewhere in the nervous system. In the ventral forebrain, Shh is necessary for the generation of cells of the medial and lateral ganglionic eminences [9]. In the midbrain and hindbrain, Shh is one of the signals necessary to generate dopaminergic and serotonergic neurons (reviewed in [6], [10]). Shh and Hh proteins play important roles in retinal and eye development in vertebrates and invertebrates, as reviewed in this issue by Peters [11], [12], [13], [14], [15], [16].

In addition to controlling cell fates, Shh promotes proliferation and inhibits differentiation of neuronal and non-neuronal cell types. One such example is the proliferative response of cerebellar granule cell neurons to Shh [17], [18], [19] (Fig. 1). Shh also regulates the proliferation and survival of oligodendrocyte precursors [20], and of neural tube and neural crest cells [21], [22] (reviewed in [23]). Hh, together with the transforming growth factor β (TGFβ)-family member Decapentaplegic (Dpp), promotes proliferation and motility of subretinal glia in the fly eye [24].

The myriad responses to Shh are achieved, in part, by controlling the production, amount, and biochemical nature of the signal itself. In addition, Hh signal transduction is regulated, so that cells respond appropriately to differing amounts of signal. Recent advances demonstrate how these strategies are employed to bring about proper developmental outcomes. Here, we discuss how covalent modifications of Shh alter its signaling activity, and how receptor trafficking may alter how cells interpret Shh signals.

Section snippets

A skinny hedgehog weighs in: the importance of cholesterol and palmitic acid modifications for Hedgehog signaling activity

The 45kD Hh precursor protein is post-translationally processed. This 22kD mature Hh signaling protein is formed by an autocatalytic cleavage that removes the carboxyl (C)-terminus. As part of this reaction, a cholesterol moiety is covalently attached to the C-terminal end of the 22kD protein [25]. Recent studies have shed light on the biological significance of this unique modification.

In Drosophila and perhaps other animals, cholesterol-modified Hh requires a transmembrane protein, called

Intracellular organelle and protein movements in Hedgehog signaling

New and intriguing observations show that subcellular protein movements occur in response to Hh signals. Several lines of evidence indicate that subcellular movements of downstream components of the Hh signaling system are important for signal transduction, both in the developing nervous system and elsewhere. We focus here on new developments involving three components of the Hh signal transduction system: the 12-transmembrane domain Ptc receptor, the seven-pass transmembrane protein Smoothened

Keeping an open brain about Hedgehog

The recent report of a new gene involved in Shh signaling, open brain (opb), further underscores the importance of lipid trafficking for Hh signaling. The opb mutant mouse strikingly resembles a partial loss-of-function ptc1 mutant mouse, with a ventralized neural tube that fails to close, abnormal cranial and eye development, and polydactyly [42], [57••]. The opb gene acts cell-autonomously in the dorsal and lateral neural tube, locations where Ptc actively represses Shh target genes [58•].

Conclusions

Neural cells respond in many ways to Shh signaling, sometimes taking on a specific cell fate and other times dividing. A goal for the future will be to better understand the mechanisms that allow distinctive responses to a rather generic signal. The potency of the signal requires that it be restrained and the inhibition by Rab23, the binding by Ptc, the opposing signal transduction effects of Ptc, and the tethering by lipophilic modifications all contribute to measured and buffered Hh

Acknowledgements

We thank Ljiljana Milenkovic and Jonathan Eggenschwiler for helpful and insightful discussions. We also thank Ljiljana Milenkovic for Fig. 1a and for her critique of the manuscript. K Ho is supported by a training grant from the National Institutes of Health. MP Scott is an Investigator of the Howard Hughes Medical Institute.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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