@article{85e976b81748424eb4ccf1c0188675a2,
title = "Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma",
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. Merk et al. show that the developmental time frame of CREBBP 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.",
keywords = "CREBBP, Rubinstein-Taybi syndrome, SHH medulloblastoma, acetyltransferase, cerebellum, development",
author = "Merk, {Daniel J.} and Jasmin Ohli and Merk, {Natalie D.} and Venu Thatikonda and Sorana Morrissy and Melanie Schoof and Schmid, {Susanne N.} and Luke Harrison and Severin Filser and Julia Ahlfeld and Serap Erkek and Kaamini Raithatha and Thomas Andreska and Marc Wei{\ss}haar and Michael Launspach and Neumann, {Julia E.} and Mehdi Shakarami and Dennis Plenker and Marra, {Marco A.} and Yisu Li and Mungall, {Andrew J.} and Moore, {Richard A.} and Yussanne Ma and Jones, {Steven J.M.} and Beat Lutz and Birgit Ertl-Wagner and Andrea Rossi and Rabea Wagener and Reiner Siebert and Andreas Jung and Eberhart, {Charles G.} and Boleslaw Lach and Michael Sendtner and Pfister, {Stefan M.} and Taylor, {Michael D.} and Lukas Chavez and Marcel Kool and Ulrich Sch{\"u}ller",
note = "Funding Information: We are indebted to Michael Schmidt, Silvia Occhionero, Marie-Christin Burmester, and Veronika Kaltenbrunn for excellent technical support, the Transcriptome and Genome Analysis Laboratory at the University Medical Center for microarray analysis, as well as expert assistance of the technical staff of the Molecular Genetics Lab of the Institute of Human Genetics Kiel. We also thank K. Hartmann from the mouse pathology core facility (UKE Hamburg, Germany) for processing immunohistochemical stainings. This work was supported by grants from the German Cancer Aid, the Wilhelm Sander-Stiftung, and the F{\"o}rdergemeinschaft Kinderkrebs-Zentrum Hamburg. The MAGIC project acknowledges financial support from Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from “The Family of Kathleen Lorette” and the Clark H. Smith Brain Tumour Centre, Montreal Children's Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, and B.R.A.I.N. Child. We also acknowledge grant support for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = mar,
day = "26",
doi = "10.1016/j.devcel.2018.02.012",
language = "English (US)",
volume = "44",
pages = "709--724.e6",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}