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.

  • Source
    • "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 · 6.27 Impact Factor
  • Source
    • " 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 ."
    [Show abstract] [Hide abstract]
    ABSTRACT: Growth differentiation factor 10 (Gdf10), also known as Bmp3b, is a member of the transforming growth factor (TGF)-ß superfamily. Gdf10 is expressed in Bergmann glial cells, which was investigated by single-cell transcriptional profiling (Koirala and Corfas, (2010) PLoS ONE 5: e9198). Here we provide a detailed characterization of Gdf10 expression from E14, the stage at which Gdf10 is expressed for the first time in the cerebellum, until P28. We detected Gdf10 expression in both germinal zones: in the ventricular zone (VZ) of the 4th ventricle as well as in the rhombic lip (RL). The VZ has been postulated to give rise to GABAergic neurons and glial cells, whereas the RL gives rise to glutamatergic neurons. Thus, it was very surprising to discover a gene that is expressed exclusively in glial cells and is not restricted to an expression in the VZ, but is also present in the RL. At postnatal stages Gdf10 was distributed equally in Bergmann glial cells of the cerebellum. Furthermore, we found Gdf10 to be regulated by Sonic hedgehog (Shh), which is secreted by Purkinje cells of the cerebellum. In the conditional Shh mutants, glial cells showed a reduced expression of Gdf10, whereas the expression of Nestin and Vimentin was unchanged. Thus, we show for the first time, that Gdf10, expressed in Bergmann glial cells, is affected by the loss of Shh as early as E18.5, suggesting a regulation of glial development by Shh. GLIA 2014.
    Glia 10/2014; 62(10). DOI:10.1002/glia.22710 · 6.03 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The study of the links and interactions between development and motor learning has noticeable implications for the understanding and management of neurodevelopmental disorders. This is particularly relevant for the cerebellum which is critical for sensorimotor learning. The olivocerebellar pathway is a key pathway contributing to learning of motor skills. Its developmental maturation and remodeling are being unraveled. Advances in genetics have led to major improvements in our appraisal of the genes involved in cerebellar development, especially studies in mutant mice. Cerebellar neurogenesis is compartmentalized in relationship with neurotransmitter fate. The Engrailed-2 gene is a major actor of the specification of cerebellar cell types and late embryogenic morphogenesis. Math1, expressed by the rhombic lip, is required for the genesis of glutamatergic neurons. Mutants deficient for the transcription factor Ptf1a display a lack of Purkinje cells and gabaergic interneurons. Rora gene contributes to the developmental signaling between granule cells and Purkinje neurons. The expression profile of sonic hedgehog in postnatal stages determines the final size/shape of the cerebellum. Genes affecting the development impact upon the physiological properties of the cerebellar circuits. For instance, receptors are developmentally regulated and their action interferes directly with developmental processes. Another field of research which is expanding relates to very preterm neonates. They are at risk for cerebellar lesions, which may themselves impair the developmental events. Very preterm neonates often show sensori-motor deficits, highlighting another major link between impaired developments and learning deficiencies. Pathways playing a critical role in cerebellar development are likely to become therapeutical targets for several neurodevelopmental disorders.
    Frontiers in Neuroanatomy 01/2012; 6:1. DOI:10.3389/fnana.2012.00001 · 4.18 Impact Factor
Show more