Merk, Daniel J., Ohli, Jasmin, Merk, Natalie D., Thatikonda, Venu, Morrissy, Sorana ORCID: 0000-0001-8526-562X, Schoof, Melanie, Schmid, Susanne N., Harrison, Luke, Filser, Severin, Ahlfeld, Julia ORCID: 0000-0002-4879-4159, Erkek, Serap ORCID: 0000-0003-4439-5203, Raithatha, Kaamini, Andreska, Thomas, Weisshaar, Marc, Launspach, Michael, Neumann, Julia E., Shakarami, Mehdi, Plenker, Dennis, Marra, Marco A., Li, Yisu, Mungall, Andrew J. ORCID: 0000-0002-0905-2742, Moore, Richard A., Ma, Yussanne, Jones, Steven J. M., Lutz, Beat, Ertl-Wagner, Birgit, Rossi, Andrea ORCID: 0000-0001-8575-700X, Wagener, Rabea, Siebert, Reiner, Jung, Andreas, Eberhart, Charles G., Lach, Boleslaw, Sendtner, Michael, Pfister, Stefan M., Taylor, Michael D., Chavez, Lukas ORCID: 0000-0002-8718-8848, Kool, Marcel and Schueller, Ulrich (2018). Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. Dev. Cell, 44 (6). S. 709 - 731. CAMBRIDGE: CELL PRESS. ISSN 1878-1551

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Merk, Daniel J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ohli, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merk, Natalie D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thatikonda, VenuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morrissy, SoranaUNSPECIFIEDorcid.org/0000-0001-8526-562XUNSPECIFIED
Schoof, MelanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmid, Susanne N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harrison, LukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Filser, SeverinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ahlfeld, JuliaUNSPECIFIEDorcid.org/0000-0002-4879-4159UNSPECIFIED
Erkek, SerapUNSPECIFIEDorcid.org/0000-0003-4439-5203UNSPECIFIED
Raithatha, KaaminiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andreska, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisshaar, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Launspach, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neumann, Julia E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shakarami, MehdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marra, Marco A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Li, YisuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mungall, Andrew J.UNSPECIFIEDorcid.org/0000-0002-0905-2742UNSPECIFIED
Moore, Richard A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ma, YussanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, Steven J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lutz, BeatUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ertl-Wagner, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rossi, AndreaUNSPECIFIEDorcid.org/0000-0001-8575-700XUNSPECIFIED
Wagener, RabeaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siebert, ReinerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jung, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eberhart, Charles G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lach, BoleslawUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sendtner, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taylor, Michael D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chavez, LukasUNSPECIFIEDorcid.org/0000-0002-8718-8848UNSPECIFIED
Kool, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schueller, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-192443
DOI: 10.1016/j.devcel.2018.02.012
Journal or Publication Title: Dev. Cell
Volume: 44
Number: 6
Page Range: S. 709 - 731
Date: 2018
Publisher: CELL PRESS
Place of Publication: CAMBRIDGE
ISSN: 1878-1551
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CELL-CYCLE EXIT; CEREBELLAR DEVELOPMENT; MOUSE MODEL; CBP GENE; EXPRESSION; MICE; MIGRATION; ACTIVATION; PRECURSORS; TUMORSMultiple languages
Cell Biology; Developmental BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19244

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item