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.
"Treatment with a Smoothened agonist, SAG resulted in an increase in surface area. These results are in agreement with previous studies that have disrupted Shh signalling (Corrales et al., 2004). Blocking of Shh signalling led to a sharp decrease in the number of perpendicular divisions and a corresponding increase in parallel divisions. "
Biology Open 05/2015; 4(7). DOI:10.1242/bio.009886 · 2.42 Impact Factor
"The mature cerebellum consists of a number of folia that grow and mature postnatally due to GCP expansion in the EGL, which is triggered by the release of SHH from Purkinje cells (Corrales et al., 2004; Lewis et al., 2004). In the rat cerebellum, Bmp4 expression is first detected in the EGL at P4 during granule cell differentiation, and is maximally expressed from P8 to P10 when differentiated granule neurons begin to migrate inwards from the EGL to their mature position in the IGL (Angley et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Purkinje cells of the developing cerebellum secrete the morphogen sonic hedgehog (SHH), which is required to maintain the proliferative state of granule cell precursors (GCPs) prior to their differentiation and migration to form the internal granule layer (IGL). Despite a wealth of knowledge regarding the function of SHH during cerebellar development, the upstream regulators of Shh expression during this process remain largely unknown. Here we report that the murine short stature homeobox 2 (Shox2) gene is required for normal Shh expression in dorsal-residing Purkinje cells. Using two different Cre drivers, we show that elimination of Shox2 in the brain results in developmental defects in the inferior colliculus and cerebellum. Specifically, loss of Shox2 in the cerebellum results in precocious differentiation and migration of GCPs from the external granule layer (EGL) to the IGL. This correlates with premature bone morphogenetic protein 4 (Bmp4) expression in granule cells of the dorsal cerebellum. The size of the neonatal cerebellum is reduced in Shox2-mutant animals, which is consistent with a reduction in the number of GCPs present in the EGL, and could account for the smaller vermis and thinner IGL present in adult Shox2-mutants. Shox2-mutant mice also display reduced exploratory activity, altered gait and impaired motor coordination. Our findings are the first to show a role for Shox2 in brain development. We provide evidence that Shox2 plays an important role during cerebellar development, perhaps to maintain the proper balance of Shh and Bmp expression levels in the dorsal vermis, and demonstrate that in the absence of Shox2, mice display both cerebellar impairments and deficits in motor coordination, ultimately highlighting the importance of Shox2 in the cerebellum.
"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). "
[Show abstract][Hide abstract] 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 · 6.46 Impact Factor
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