Flora A, Klisch TJ, Schuster G, Zoghbi HY.. Deletion of Atoh1 disrupts Sonic Hedgehog signaling in the developing cerebellum and prevents medulloblastoma. Science 326: 1424-1427

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Science (Impact Factor: 33.61). 12/2009; 326(5958):1424-7. DOI: 10.1126/science.1181453
Source: PubMed


Granule neuron precursors (GNPs) are the most actively proliferating cells in the postnatal nervous system, and mutations in pathways that control the GNP cell cycle can result in medulloblastoma. The transcription factor Atoh1 has been suspected to contribute to GNP proliferation, but its role in normal and neoplastic postnatal cerebellar development remains unexplored. We show that Atoh1 regulates the signal transduction pathway of Sonic Hedgehog, an extracellular factor that is essential for GNP proliferation, and demonstrate that deletion of Atoh1 prevents cerebellar neoplasia in a mouse model of medulloblastoma. Our data shed light on the function of Atoh1 in postnatal cerebellar development and identify a new mechanism that can be targeted to regulate medulloblastoma formation.

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    • "We have also scrutinized the list of Atoh1 neuronal targets that are repressed in iHCs, and two genes are worthy of mention – Gli2 and Foxm1, which are known to be crucial for Shh-driven proliferation of CGPs (Flora et al., 2009). Repression of these genes in iHCs illustrates how the combination of Atoh1 with Gfi1 and Pou4f3 leads to key differences in gene expression, with likely functional consequences: whereas Atoh1 induction of Gli2 in CGPs allows these cells to proliferate in response to Shh (Flora et al., 2009), Gli2 repression in iHCs might shield these cells from Shh and contribute to the rapid cell cycle exit that we observed after induction of the three TFs. "
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    ABSTRACT: Mechanosensory hair cells (HCs) are the primary receptors of our senses of hearing and balance. Elucidation of the transcriptional networks regulating HC fate determination and differentiation is crucial not only to understand inner ear development but also to improve cell replacement therapies for hearing disorders. Here, we show that combined expression of the transcription factors Gfi1, Pou4f3 and Atoh1 can induce direct programming towards HC fate, both during in vitro mouse embryonic stem cell differentiation and following ectopic expression in chick embryonic otic epithelium. Induced HCs (iHCs) express numerous HC-specific markers and exhibit polarized membrane protrusions reminiscent of stereociliary bundles. Transcriptome profiling confirms the progressive establishment of a HC-specific gene signature during in vitro iHC programming. Overall, this work provides a novel approach to achieve robust and highly efficient HC production in vitro, which could be used as a model to study HC development and to drive inner ear HC regeneration. © 2015. Published by The Company of Biologists Ltd.
    Development 06/2015; 142(11):1948-59. DOI:10.1242/dev.119149 · 6.46 Impact Factor
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    • "Consistent with these results, Gli2, which encodes the main transcriptional effector of Shh signaling in GNPs (Lewis et al., 2004; Wechsler-Reya and Scott, 1999), is downstream of Atoh1, having 8 E-boxes in its second intron, which is proved to be an active transcriptional enhancer (Flora et al., 2009) (Table 1). Deletion of Atoh1 is able to abolish the SHH response, the mitogenic signal in GNP, preventing medulloblastoma formation in the cerebellum (Flora et al., 2009). "
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    ABSTRACT: Atoh1, Hes1 and Hes5 are crucial for normal inner ear hair cell development. They regulate the expression of each other in a complex network, while they also interact with many other genes and pathways, such as Notch, FGF, SHH, WNT, BMP and RA. This paper summarized molecular pathways that involve Atoh1, Hes1, and Hes5. Some of pathways and gene regulation mechanisms discussed here were studied in other tissues, yet they might inspire studies in inner ear hair cell development. Thereby, we presented a complex regulatory network involving these three genes, which might be crucial for proliferation and differentiation of inner ear hair cells. Copyright © 2014. Published by Elsevier B.V.
    Gene 12/2014; 558(1). DOI:10.1016/j.gene.2014.12.054 · 2.14 Impact Factor
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    • "Balancing proliferation and differentiation in the external germinal layer The EGL (Fig. 4) is defined by its transience and proliferation, and by the expression of the bHLH transcription factor Atoh1 (Akazawa et al., 1995; Ben-Arie et al., 1996, 1997), which is absolutely required both for transit amplification (Flora et al., 2009) and for supressing differentiation (Klisch et al., 2011). In mouse, the EGL persists until the third week of postnatal life, and the peak of proliferation occurs around birth (Espinosa and Luo, 2008). "
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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 · 6.46 Impact Factor
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