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Opposing effects of CREBBP mutations govern the phenotype of Rubinstein-Taybi syndrome and adult SHH medulloblastoma

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 si...

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Main Authors: Merk, Daniel J. (Author) , Ohli, Jasmin (Author) , Merk, Natalie D. (Author) , Thatikonda, Venu (Author) , Morrissy, Sorana (Author) , Schoof, Melanie (Author) , Schmid, Susanne N. (Author) , Harrison, Luke (Author) , Filser, Severin (Author) , Ahlfeld, Julia (Author) , Erkek, Serap (Author) , Raithatha, Kaamini (Author) , Andreska, Thomas (Author) , Weißhaar, Marc (Author) , Launspach, Michael (Author) , Neumann, Julia E. (Author) , Shakarami, Mehdi (Author) , Plenker, Dennis (Author) , Marra, Marco A. (Author) , Li, Yisu (Author) , Mungall, Andrew J. (Author) , Moore, Richard A. (Author) , Ma, Yussanne (Author) , Jones, Steven J. M. (Author) , Lutz, Beat (Author) , Ertl-Wagner, Birgit (Author) , Rossi, Andrea (Author) , Wagener, Rabea (Author) , Siebert, Reiner (Author) , Jung, Andreas (Author) , Eberhart, Charles G. (Author) , Lach, Boleslaw (Author) , Sendtner, Michael (Author) , Pfister, Stefan (Author) , Taylor, Michael D. (Author) , Chavez, Lukas (Author) , Kool, Marcel (Author) , Schüller, Ulrich (Author)
Format: Article (Journal)
Language:English
Published: March 15, 2018
In: Developmental cell
Year: 2018, Volume: 44, Issue: 6, Pages: 709-724, e1-e6
ISSN:1878-1551
DOI:10.1016/j.devcel.2018.02.012
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.devcel.2018.02.012
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Author Notes: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 Li, Andrew 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, and Ulrich Schüller

MARC

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520 |a 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. 
650 4 |a acetyltransferase 
650 4 |a Acetyltransferases 
650 4 |a Adult 
650 4 |a Animals 
650 4 |a Cerebellar Neoplasms 
650 4 |a cerebellum 
650 4 |a CREB-Binding Protein 
650 4 |a CREBBP 
650 4 |a development 
650 4 |a Female 
650 4 |a Hedgehog Proteins 
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650 4 |a Mice 
650 4 |a Mice, Knockout 
650 4 |a Mutation 
650 4 |a Neurons 
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