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 journalArticle

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

Fingerprint

Rubinstein-Taybi Syndrome
Medulloblastoma
Neurons
Phenotype
Mutation
Hedgehogs
Cerebellum
Acetyltransferases
Brain-Derived Neurotrophic Factor
Chromatin
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Germ-Line Mutation
Chemical activation
Embryonic Development
Down-Regulation
Growth

Keywords

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

ASJC Scopus subject areas

  • Developmental Biology

Cite this

Merk, D. J., Ohli, J., Merk, N. D., Thatikonda, V., Morrissy, S., Schoof, M., ... Schüller, U. (2018). Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. Developmental Cell, 44(6), 709-724.e6. https://doi.org/10.1016/j.devcel.2018.02.012

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: Developmental Cell, Vol. 44, No. 6, 26.03.2018, p. 709-724.e6.

Research output: Contribution to journalArticle

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', Developmental Cell, vol. 44, no. 6, pp. 709-724.e6. https://doi.org/10.1016/j.devcel.2018.02.012
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. / Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma. In: Developmental Cell. 2018 ; Vol. 44, No. 6. pp. 709-724.e6.
@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 = "acetyltransferase, cerebellum, CREBBP, development, Rubinstein-Taybi syndrome, SHH medulloblastoma",
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",
year = "2018",
month = "3",
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",

}

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

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. 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.

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. 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.

KW - acetyltransferase

KW - cerebellum

KW - CREBBP

KW - development

KW - Rubinstein-Taybi syndrome

KW - SHH medulloblastoma

UR - http://www.scopus.com/inward/record.url?scp=85043361465&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85043361465&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2018.02.012

DO - 10.1016/j.devcel.2018.02.012

M3 - Article

C2 - 29551561

AN - SCOPUS:85043361465

VL - 44

SP - 709-724.e6

JO - Developmental Cell

JF - Developmental Cell

SN - 1534-5807

IS - 6

ER -