Article

Spatial pattern of sonic hedgehog signaling through Gli genes during cerebellum development

Howard Hughes Medical Institute, Ashburn, Virginia, United States
Development (Impact Factor: 6.27). 12/2004; 131(22):5581-90. DOI: 10.1242/dev.01438
Source: PubMed

ABSTRACT The cerebellum consists of a highly organized set of folia that are largely generated postnatally during expansion of the granule cell precursor (GCP) pool. Since the secreted factor sonic hedgehog (Shh) is expressed in Purkinje cells and functions as a GCP mitogen in vitro, it is possible that Shh influences foliation during cerebellum development by regulating the position and/or size of lobes. We studied how Shh and its transcriptional mediators, the Gli proteins, regulate GCP proliferation in vivo, and tested whether they influence foliation. We demonstrate that Shh expression correlates spatially and temporally with foliation. Expression of the Shh target gene Gli1 is also highest in the anterior medial cerebellum, but is restricted to proliferating GCPs and Bergmann glia. By contrast, Gli2 is expressed uniformly in all cells in the developing cerebellum except Purkinje cells and Gli3 is broadly expressed along the anteroposterior axis. Whereas Gli mutants have a normal cerebellum, Gli2 mutants have greatly reduced foliation at birth and a decrease in GCPs. In a complementary study using transgenic mice, we show that overexpressing Shh in the normal domain does not grossly alter the basic foliation pattern, but does lead to prolonged proliferation of GCPs and an increase in the overall size of the cerebellum. Taken together, these studies demonstrate that positive Shh signaling through Gli2 is required to generate a sufficient number of GCPs for proper lobe growth.

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    • "The tempo of transit amplification within the EGL is driven by diffusible sonic hedgehog (Shh) secreted by underlying Purkinje cells (Dahmane and Ruiz-i-Altaba, 1999; Wallace, 1999; Wechsler-Reya and Scott, 1999; Lewis et al., 2004), and the importance of this pathway in a subset of medulloblastomas has been established through a variety of experimental and genomic methodologies (Box 3). Elegant studies manipulating the Shh signalling pathway appear to confirm the idea that foliation is a product of the surface expansion generated by transit amplification (Corrales et al., 2004, 2006). Proliferation within the EGL has also been shown to be influenced by a number of extracellular matrix (ECM) components, such as β1- integrin, that are expressed both within the EGL (Blaess et al., 2004) and in cerebellar Bergmann glial cells (see Glossary, Box 1) (Frick et al., 2012). "
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    ABSTRACT: The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.
    Development 11/2014; 141(21):4031-4041. DOI:10.1242/dev.106559 · 6.27 Impact Factor
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    • " glial cell development due to a disrupted Purkinje cell develop - ment at postnatal stages . Furthermore Gli1 and Gli2 , two of the most prominent down stream targets of the Shh signaling machinery , are both expressed in Bergmann glial cells and although Bergmann glia form in Gli2 conditional knock - out mutants , their fibers are disorganized ( Corrales et al . , 2004 ) . This additionally supports our hypothesis that Shh signaling could have a direct effect on Bergmann glia differentiation ."
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    Glia 10/2014; 62(10). DOI:10.1002/glia.22710 · 6.03 Impact Factor
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    • "For instance, sonic hedgehog stimulates very strongly the proliferation of cerebellar granular neuronal precursors through the induction and repression of cell cycle regulators genes (Wechsler-Reya and Scott, 1999). Blocking GLI2 causes a failure in the development of cerebellar granular neuronal precursors, ending in cerebellar hypoplasia (Corrales et al., 2004). In addition, sonic hedgehog contributes to cerebellar cortex development by promoting Bergmann glia proliferation and thus contributing to the migration support (Corrales et al., 2006; Vaillant and Monard, 2009). "
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