Hedgehog (Hh) signaling plays an integral role in promoting proliferation in cerebellar granule cell precursors, which multiply in an external layer before differentiating and migrating deeper into the cerebellum. Overactivation of the Hh pathway is associated with medulloblastoma, a pediatric brain tumor that arises when granule cells continue to proliferate rather than differentiate. Genetic lesions commonly associated with human medulloblastoma include mutations in patched 1 (Ptch1), which encodes a Hh receptor, and loss of heterozygosity of hypermethylated in cancer 1 (Hic1), which encodes a transcriptional repressor. Briggs et al. propose that Hic1 attenuates the Hh proliferation signal by repressing expression of Atonal homolog 1 (Atoh1), a proneural transcription factor. Compound heterozygous mice carrying one deletion allele each of Ptch1 and Hic1 had an increased incidence of medulloblastoma as compared with animals carrying only one allele. Microarray analysis identified many potential targets of Hic1 regulation, one of which was Atoh1, a putative target of Hh signaling expressed in granule cell precursors and medulloblastomas. Chromatin immunoprecipitation experiments showed a direct interaction between Hic1 and the Atoh1 enhancer, and experiments in cell culture demonstrated that Hic1-mediated repression of Atoh1 expression overcomes its activation by Shh. Taken together, these data suggest a model in which Hh signaling induces proliferation of granule cells by activating Atoh1 expression, and differentiation is initiated when Hic1 represses Atoh1 expression. In the context of neural development, signaling through bone morphogenetic protein (BMP) pathways antagonizes Hh signaling to induce differentiation. In a related article, Zhao et al. (see commentary by Grimmer and Weiss) report that BMP signaling stimulated proteolytic degradation of Atoh1 in medulloblastoma and granule cells. Redundant mechanisms for reducing the abundance of Atoh1 may ensure that granule cells are insensitive to proliferation signals during terminal differentiation and identify Atoh1 as a potentially important target for medulloblastoma therapies.
K. J. Briggs, I. M. Corcoran-Schwartz, W. Zhang, T. Harcke, W. L. Devereux, S. B. Baylin, C. G. Eberhart, D. N. Watkins, Cooperation between the Hic1 and Ptch1 tumor suppressors in medulloblastoma. Genes & Dev. 22, 770-785 (2008). [Abstract] [Full Text]
H. Zhao, O. Ayrault, F. Zindy, J.-H. Kim, M. F. Roussel, Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development. Genes & Dev. 22, 722-727 (2008). [Abstract] [Full Text]
M. R. Grimmer, W. A. Weiss, BMPs oppose Math1 in cerebellar development and in medulloblastoma. Genes & Dev. 22, 693-699 (2008). [Full Text]