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

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

In: DEV CELL, Vol. 44, No. 6, 26.03.2018, p. 709-724.e6.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Merk, DJ, Ohli, J, Merk, ND, Thatikonda, V, Morrissy, S, Schoof, M, Schmid, SN, Harrison, L, Filser, S, Ahlfeld, J, Erkek, S, Raithatha, K, Andreska, T, Weißhaar, M, Launspach, M, Neumann, JE, Shakarami, M, Plenker, D, Marra, MA, Li, Y, Mungall, AJ, Moore, RA, Ma, Y, Jones, SJM, Lutz, B, Ertl-Wagner, B, Rossi, A, Wagener, R, Siebert, R, Jung, A, Eberhart, CG, Lach, B, Sendtner, M, Pfister, SM, Taylor, MD, Chavez, L, Kool, M & Schüller, U 2018, 'Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma', DEV CELL, vol. 44, no. 6, pp. 709-724.e6. https://doi.org/10.1016/j.devcel.2018.02.012

APA

Merk, D. J., Ohli, J., Merk, N. D., Thatikonda, V., Morrissy, S., Schoof, M., Schmid, S. N., Harrison, L., Filser, S., Ahlfeld, J., Erkek, S., Raithatha, K., Andreska, T., Weißhaar, M., Launspach, M., Neumann, J. E., Shakarami, M., Plenker, D., Marra, M. A., ... Schüller, U. (2018). Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. DEV CELL, 44(6), 709-724.e6. https://doi.org/10.1016/j.devcel.2018.02.012

Vancouver

Merk DJ, Ohli J, Merk ND, Thatikonda V, Morrissy S, Schoof M et al. Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. DEV CELL. 2018 Mar 26;44(6):709-724.e6. https://doi.org/10.1016/j.devcel.2018.02.012

Bibtex

@article{16661290fc29475699cae1ff872e6db2,
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.",
keywords = "Journal Article",
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 = "Copyright {\textcopyright} 2018 Elsevier Inc. All rights reserved.",
year = "2018",
month = mar,
day = "26",
doi = "10.1016/j.devcel.2018.02.012",
language = "English",
volume = "44",
pages = "709--724.e6",
journal = "DEV CELL",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",

}

RIS

TY - JOUR

T1 - Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma

AU - Merk, Daniel J

AU - Ohli, Jasmin

AU - Merk, Natalie D

AU - Thatikonda, Venu

AU - Morrissy, Sorana

AU - Schoof, Melanie

AU - Schmid, Susanne N

AU - Harrison, Luke

AU - Filser, Severin

AU - Ahlfeld, Julia

AU - Erkek, Serap

AU - Raithatha, Kaamini

AU - Andreska, Thomas

AU - Weißhaar, Marc

AU - Launspach, Michael

AU - Neumann, Julia E

AU - Shakarami, Mehdi

AU - Plenker, Dennis

AU - Marra, Marco A

AU - Li, Yisu

AU - Mungall, Andrew J

AU - Moore, Richard A

AU - Ma, Yussanne

AU - Jones, Steven J M

AU - Lutz, Beat

AU - Ertl-Wagner, Birgit

AU - Rossi, Andrea

AU - Wagener, Rabea

AU - Siebert, Reiner

AU - Jung, Andreas

AU - Eberhart, Charles G

AU - Lach, Boleslaw

AU - Sendtner, Michael

AU - Pfister, Stefan M

AU - Taylor, Michael D

AU - Chavez, Lukas

AU - Kool, Marcel

AU - Schüller, Ulrich

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/3/26

Y1 - 2018/3/26

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.devcel.2018.02.012

DO - 10.1016/j.devcel.2018.02.012

M3 - SCORING: Journal article

C2 - 29551561

VL - 44

SP - 709-724.e6

JO - DEV CELL

JF - DEV CELL

SN - 1534-5807

IS - 6

ER -