Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma

Daniel J. Merk, Jasmin Ohli, Natalie D. Merk, Venu Thatikonda, Sorana Morrissy, Melanie Schoof, Susanne N. Schmid, Luke Harrison, Severin Filser, Julia Ahlfeld, Serap Erkek, Kaamini Raithatha, Thomas Andreska, Marc Weißhaar, Michael Launspach, Julia E. Neumann, Mehdi Shakarami, Dennis Plenker, Marco A. Marra, Yisu LiAndrew J. Mungall, Richard A. Moore, Yussanne Ma, Steven J.M. Jones, Beat Lutz, Birgit Ertl-Wagner, Andrea Rossi, Rabea Wagener, Reiner Siebert, Andreas Jung, Charles G. Eberhart, Boleslaw Lach, Michael Sendtner, Stefan M. Pfister, Michael D. Taylor, Lukas Chavez, Marcel Kool, Ulrich Schüller

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)709-724.e6
JournalDevelopmental Cell
Volume44
Issue number6
DOIs
StatePublished - Mar 26 2018

Keywords

  • CREBBP
  • Rubinstein-Taybi syndrome
  • SHH medulloblastoma
  • acetyltransferase
  • cerebellum
  • development

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma'. Together they form a unique fingerprint.

Cite this