Developmental Cell, 26 March 2018, Vol.44(6), pp.709-724.e6
Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor ( ). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of . By contrast, loss of in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of mutations and corresponding associations with human diseases. Merk et al. show that the developmental time frame of mutation acquisition in cerebellar granule neurons determines the pathogenic effect of these alterations in the cerebellum. These time-sensitive consequences explain phenotypic differences seen in patients with germline (Rubinstein-Taybi syndrome) or somatic mutations (adult SHH medulloblastoma) of .
Crebbp ; Acetyltransferase ; Cerebellum ; Rubinstein-Taybi Syndrome ; Shh Medulloblastoma ; Development ; Biology
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