Hedgehog trafficking, cilia and brain functions

doi:10.1016/j.diff.2011.11.011

Differentiation

Volume 83, Issue 2, February 2012, Pages S97-S104

https://doi.org/10.1016/j.diff.2011.11.011 Get rights and content

Abstract

The primary cilium has recently emerged as an important center for transduction of the Sonic Hedgehog (Shh) signal. Genetic studies have shown that Shh signaling at the level of primary cilia is essential for patterning the ventral neural tube and regulating adult stem cells. Some defects observed in human diseases and resulting from mutations affecting the organization of the primary cilium have been attributed to defective Shh signaling. The recent development of Shh pathway inhibitors for treating tumors linked to perturbations of Shh signaling has fostered studies to understand their mechanism of action in Shh receptor complex trafficking at the primary cilium.

Introduction

The Sonic Hedgehog (Shh) signaling pathway is well known for its roles in patterning and growth of brain structures during development (Dessaud et al., 2008, Varjosalo and Taipale, 2008). The early discovery of Shh expression throughout the adult rodent brain (Traiffort et al., 2010, Traiffort et al., 1998) has generated considerable interest and novel functions for this protein have progressively emerged (Borzillo and Lippa, 2005, Traiffort et al., 2010). The importance of Shh signaling in adult brain plasticity is demonstrated by its implication in neural stem cell maintenance in adult neurogenic niches (Han and Alvarez-Buylla, 2010, Suh et al., 2009). Humans affected by the Gorlin syndrome have inactivating mutations in the key Shh receptor Patched (Ptc), characterized as a negative regulator of Shh signaling. They display susceptibility to develop medulloblastoma, one of the most malignant brain tumors in childhood. As a consequence of these mutations, the Ptc-mediated inhibition exerted on the Smoothened (Smo) receptor, the main positive regulator of the pathway, is relieved, leading to the tumorigenic process. Thus, inhibiting the Shh signaling pathway by small molecule inhibitors has generated considerable interest for treating these tumors, and several inhibitors of Smo are currently being evaluated for treating medulloblastomas (Heretsch et al., 2010, Mas and Ruiz i Altaba, 2010, Scales and de Sauvage, 2009). The recent discovery that Shh signaling depends on primary cilia (Huangfu et al., 2003) has fostered studies aimed at characterizing the distribution and the regulation of the pathway at the level of this important signaling center (Goetz and Anderson, 2010, Louvi and Grove, 2011, Simpson et al., 2009). Genetic studies in mice showed that Shh signaling at the level of the primary cilium is essential for patterning of the ventral neural tube in the mouse embryo but also in the regulation of adult stem cells (Han and Alvarez-Buylla, 2010). In addition, some defects in human diseases known as ciliopathies and resulting from mutations affecting the organization of the primary cilia, have been attributed to defective Hedgehog (Hh) signaling (Goetz and Anderson, 2010). Here, we review the role of Hh signaling and trafficking at the primary cilium during brain development and in mature neural tissues. We also highlight its importance for treating brain tumors and understanding the complex traits of several human disorders linked to primary cilia defects.

Section snippets

Transduction of Hh signaling at the primary cilium

In vertebrates, the primary cilium is defined as a microtubule-based organelle of about 1–5 μm in length. It extends from the cell surface as a single, non motile, antenna-like structure and is present on most cell types in embryonic and adult tissues (Bettencourt-Dias et al., 2011, Louvi and Grove, 2011). The ciliary basal body is formed from the mother centriole and acts as a docking area for a large number of pericentriolar proteins. The axoneme, constituted by nine doublets of microtubules,

Hh ciliary dysfunction and human diseases affecting neural tissues

Recent studies have investigated the link between the dysfunction of primary cilia and Hh signaling in human ciliopathies and in related mouse models (Simpson et al., 2009) (Table 1). Several components of the mouse IFT machinery required for the assembly and maintenance of cilia were reported from a mutant screen to be essential for the specification of Shh-dependent ventral cell types in the neural tube. They include the IFTB complex components IFT172, IFT88 and the IFT-dedicated retrograde

Cilia, Hh signaling and hippocampal development

Recent advances in adult neurogenesis have highlighted the capacity of the brain to generate new neurons throughout adult life. Stem cells have been characterized in several regions of the adult brain including the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (Kriegstein and Alvarez-Buylla, 2009, Zhao et al., 2008). Both neurogenic niches contain astrocytes displaying features of slow-dividing adult neural stem cells that give rise to

Cilia, Hh signaling and cerebellum development

Granule neurons in the cerebellum represent the most abundant neurons in the adult brain and arise from granule cell precursors (GCPs) located in the rhombic lip. From this germinal center, GCPs migrate into the external granule cell layer (EGL) and proliferate during the first two weeks after birth to produce granule neurons. In the postnatal maturing cerebellum, Shh from the Purkinje cells is a potent mitogen for GCPs (Traiffort et al., 2010). This effect presumably occurs through the

Astrocytes, cilia and Hh signaling

Astrocytes play diverse essential roles in CNS during embryogenesis through regulation of synapse formation and function as well as by promoting dendritic spine maturation. In adulthood, they are proposed as key elements in synaptic transmission (Stipursky et al., 2011). Several studies indicate that Hh signaling is active in astrocytes both during development and in the more mature brain. It is responsible for the proliferation of astrocyte precursors in the developing chick optic nerve (

Cilia and Hh signaling in brain tumors

Abnormal proliferation of cerebellar GCPs are associated with the development of medulloblastoma. These tumors were initially considered as Hh ligand-independent since aberrant signaling activation is linked to pathway-activating mutations in Ptc, Sufu or Smo (Scales and de Sauvage, 2009). Humans affected by the Gorlin syndrome display a higher incidence of medulloblastomas. Gorlin syndrome is an autosomal dominantly inherited disorder characterized by Ptc inactivating mutations that results in

Smo trafficking at the primary cilia is regulated by Hh inhibitors

Cyclopamine and several other small-molecule inhibitors of the Hh pathway (Fig. 2B) have been developed and proposed for the treatment of cancers associated with dysfunctions of Hh signaling. Most of these molecules, but not all, target Smo (Heretsch et al., 2010, Scales and de Sauvage, 2009). Among them, Cur61414 or HhAntag691 have been shown to induce remission in animal models of medulloblastoma. Recently, clinical trials for treating basal cell carcinoma and medulloblastoma in human have

Conclusions

The functional roles of the Shh signaling pathway in the developing and adult CNS range from regulation of stem and precursor cells to the modulation of electrophysiological activity of neurons (Bezard et al., 2003, Pascual et al., 2005). Increasing evidences have shown that Shh signaling depends on the primary cilium. Progress has still to be made for further understanding the molecular and biochemical events controlling Hh pathway trafficking at this important signaling center. Besides

Acknowledgment

We thank S. O’Reagan for her comments on the manuscript. This work was supported by La Ligue Contre Le Cancer to M.R. (comité de l’Essonne) and by a fellowship from DGA to J.F.

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The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild “molar tooth sign”), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies.
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Hedgehog trafficking, cilia and brain functions

Abstract

Introduction

Section snippets

Transduction of Hh signaling at the primary cilium

Hh ciliary dysfunction and human diseases affecting neural tissues

Cilia, Hh signaling and hippocampal development

Cilia, Hh signaling and cerebellum development

Astrocytes, cilia and Hh signaling

Cilia and Hh signaling in brain tumors

Smo trafficking at the primary cilia is regulated by Hh inhibitors

Conclusions

Acknowledgment

Developmental Cell

Trends in Cell Biology

The Journal of Biological Chemistry

Trends in Genetics

Journal of Physiology (Paris)

Molecular and Cellular Neuroscience

Developmental Biology

Cell

American Journal of Human Genetics

Current Biology

Current Opinion in Neurobiology

Bioorganic and Medicinal Chemistry

Neuron

Developmental Cell

Neuron

Neuron

Biochemical Pharmacology

Developmental Biology

Cancer Genetics and Cytogenetics

Trends in Cell Biology

Trends in Pharmacological Sciences

Developmental Biology

Mechanisms of Development

Developmental Biology

Life Sciences

The Journal of Biological Chemistry

The Journal of Biological Chemistry

Cell

In vivo analysis of quiescent adult neural stem cells responding to Sonic Hedgehog

Nature

Primary cilia regulate proliferation of amplifying progenitors in adult hippocampus: implications for learning and memory

The Journal of Neuroscience

Chemoattractive activity of sonic hedgehog in the adult subventricular zone modulates the number of neural precursors reaching the olfactory bulb

Stem Cells

Sonic Hedgehog signaling in astrocytes is dependent on p38 mitogen-activated protein kinase and G-protein receptor kinase 2

Journal of Neurochemistry

Recruitment of the Sonic Hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis

European Journal of Neuroscience

Sonic Hedgehog signaling is decoded by calcium spike activity in the developing spinal cord

Proceedings of the National Academy of Sciences

Sonic Hedgehog is a neuromodulator in the adult subthalamic nucleus

FASEB Journal

Type III adenylyl cyclase localizes to primary cilia throughout the adult mouse brain

The Journal of Comparative Neurology

The Hedgehog signaling pathway as a target for anticancer drug discovery

Current Topics in Medicinal Chemistry

Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling

Proceedings of the National Academy of Sciences

Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma

Science Translational Medicine

Notochord-derived Shh concentrates in close association with the apically positioned basal body in neural target cells and forms a dynamic gradient during neural patterning

Development

Intrastriatal Sonic Hedgehog injection increases patched transcript levels in the adult rat subventricular zone

The Journal of Neuroscience

Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened

Genes and Development

Vertebrate Smoothened functions at the primary cilium

Nature

Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice

Cancer Research

Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

The Journal of Clinical Investigation

Sonic hedgehog regulates the growth and patterning of the cerebellum

Development

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Nature Genetics

Pattern formation in the vertebrate neural tube: a sonic Hedgehog morphogen-regulated transcriptional network