Hedgehog trafficking, cilia and brain functions
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.
References (98)
- et al.
Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function
Developmental Cell
(2011) - et al.
Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling
Trends in Cell Biology
(2010) - et al.
Sonic Hedgehog-induced proliferation requires specific Galpha inhibitory proteins
The Journal of Biological Chemistry
(2011) - et al.
Centrosomes and cilia in human disease
Trends in Genetics
(2011) - et al.
Sonic Hedgehog signalling in the developing and adult brain
Journal of Physiology (Paris)
(2002) - et al.
Hedgehog interacting protein in the mature brain: membrane-associated and soluble forms
Molecular and Cellular Neuroscience
(2004) - et al.
Analysis of talpid3 and wild-type chicken embryos reveals roles for Hedgehog signalling in development of the limb bud vasculature
Developmental Biology
(2007) - et al.
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Cell
(1999) - et al.
Disruption of a ciliary B9 protein complex causes Meckel syndrome
American Journal of Human Genetics
(2011) - et al.
The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development
Current Biology
(2009)
Role of primary cilia in brain development and cancer
Current Opinion in Neurobiology
Modulators of the Hedgehog signaling pathway
Bioorganic and Medicinal Chemistry
Persistent Sonic Hedgehog signaling in adult brain determines neural stem cell positional identity
Neuron
Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation
Developmental Cell
Cilia in the CNS: the quiet organelle claims center stage
Neuron
Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches
Neuron
Small molecule modulation of HH-GLI signaling: current leads, trials and tribulations
Biochemical Pharmacology
Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli
Developmental Biology
Methylation of PTCH1, the Patched-1 gene, in a panel of primary medulloblastomas
Cancer Genetics and Cytogenetics
The Gli code: an information nexus regulating cell fate, stemness and cancer
Trends in Cell Biology
Mechanisms of Hedgehog pathway activation in cancer and implications for therapy
Trends in Pharmacological Sciences
BMP7 and SHH regulate Pax2 in mouse retinal astrocytes by relieving TLX repression
Developmental Biology
Trafficking, development and Hedgehog
Mechanisms of Development
Primary cilia are required for cerebellar development and Shh-dependent expansion of progenitor pool
Developmental Biology
Neuron-glia signaling: Implications for astrocyte differentiation and synapse formation
Life Sciences
Biochemical mapping of interactions within the intraflagellar transport (IFT) B core complex: IFT52 binds directly to four other IFT-B subunits
The Journal of Biological Chemistry
Functional characterization of Sonic Hedgehog mutations associated with holoprosencephaly
The Journal of Biological Chemistry
Mechanisms and functional implications of adult neurogenesis
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
Development
Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh
Nature Neuroscience
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