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Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma.
- Source :
-
Developmental cell [Dev Cell] 2018 Mar 26; Vol. 44 (6), pp. 709-724.e6. Date of Electronic Publication: 2018 Mar 15. - Publication Year :
- 2018
-
Abstract
- 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 CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Animals
CREB-Binding Protein genetics
Cerebellar Neoplasms genetics
Cerebellar Neoplasms metabolism
Cerebellar Neoplasms pathology
Female
Hedgehog Proteins genetics
Humans
Medulloblastoma genetics
Medulloblastoma metabolism
Mice
Mice, Knockout
Neurons
Phenotype
Rubinstein-Taybi Syndrome genetics
Rubinstein-Taybi Syndrome metabolism
Signal Transduction
Acetyltransferases metabolism
CREB-Binding Protein metabolism
CREB-Binding Protein physiology
Hedgehog Proteins metabolism
Medulloblastoma pathology
Mutation
Rubinstein-Taybi Syndrome pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1551
- Volume :
- 44
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Developmental cell
- Publication Type :
- Academic Journal
- Accession number :
- 29551561
- Full Text :
- https://doi.org/10.1016/j.devcel.2018.02.012