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

被引：38

作者：

Merk, Daniel J. ^{[1
,2
,3
]}

Ohli, Jasmin ^{[1
]}

Merk, Natalie D. ^{[4
]}

Thatikonda, Venu ^{[5
]}

Morrissy, Sorana ^{[6
,7
,8
]}

Schoof, Melanie ^{[9
]}

Schmid, Susanne N. ^{[1
,10
]}

Harrison, Luke ^{[1
]}

Filser, Severin ^{[11
]}

Ahlfeld, Julia ^{[1
,12
]}

Erkek, Serap ^{[5
,13
,14
]}

Raithatha, Kaamini ^{[15
]}

Andreska, Thomas ^{[16
]}

Weisshaar, Marc ^{[1
]}

Launspach, Michael ^{[1
]}

Neumann, Julia E. ^{[1
,17
]}

Shakarami, Mehdi ^{[18
]}

Plenker, Dennis ^{[19
]}

Marra, Marco A. ^{[20
,21
]}

Li, Yisu ^{[10
]}

Mungall, Andrew J. ^{[20
]}

Moore, Richard A. ^{[20
]}

Ma, Yussanne ^{[20
]}

Jones, Steven J. M. ^{[20
]}

Lutz, Beat ^{[22
]}

Ertl-Wagner, Birgit ^{[23
]}

Rossi, Andrea ^{[24
]}

Wagener, Rabea ^{[25
,26
,27
,28
]}

Siebert, Reiner ^{[25
,26
,27
,28
]}

Jung, Andreas ^{[29
]}

Eberhart, Charles G. ^{[30
,31
]}

Lach, Boleslaw ^{[32
]}

Sendtner, Michael ^{[16
]}

Pfister, Stefan M. ^{[5
,33
]}

Taylor, Michael D. ^{[6
,7
,8
,34
]}

Chavez, Lukas ^{[5
]}

Kool, Marcel ^{[5
,14
]}

Schueller, Ulrich ^{[1
,9
,17
,35
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Ctr Neuropathol, D-81377 Munich, Germany

[2] Dana Farber Canc Inst, Canc Biol & Pediat Oncol, Boston, MA 02215 USA

[3] Harvard Med Sch, Neurobiol, Boston, MA 02215 USA

[4] Tech Univ Munich, Munich Ctr Integrated Prot Sci, Chem Dept, D-85747 Munich, Germany

[5] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany

[6] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1L7, Canada

[7] Hosp Sick Children, Div Neurosurg, Toronto, ON M5G 1L7, Canada

[8] HSC, Program Dev & Stem Cell Biol, Toronto, ON M5G 1X8, Canada

[9] Childrens Canc Ctr Hamburg, Res Inst, Martinistr 52,N63 HPI, D-20251 Hamburg, Germany

[10] Univ Med Ctr Gottingen, Dept Neuropathol, D-37099 Gottingen, Germany

[11] Ludwig Maximilians Univ Munchen, German Ctr Neurodegenerat Dis DZNE, D-81377 Munich, Germany

[12] Ludwig Maximilians Univ Munchen, Dept Internal Med 4, Div Clin Pharmacol, D-80337 Munich, Germany

[13] EMBL, Genome Biol Unit, D-69117 Heidelberg, Germany

[14] German Canc Consortium DKTK, Core Ctr Heidelberg, D-69120 Heidelberg, Germany

[15] Univ Med Ctr Gottingen, Microarray & Deep Sequencing Core Facil, D-37077 Gottingen, Germany

[16] Univ Wurzburg, Inst Clin Neurobiol, D-97078 Wurzburg, Germany

[17] Univ Med Ctr, Inst Neuropathol, D-20246 Hamburg, Germany

[18] Ludwig Maximilians Univ Munchen, Walter Brendel Ctr Expt Med, D-81377 Munich, Germany

[19] Univ Cologne, Dept Translat Genom, D-50931 Cologne, Germany

[20] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC VSZ 4S6, Canada

[21] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[22] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Physiol Chem, D-55128 Mainz, Germany

[23] Ludwig Maximilians Univ Munchen, Inst Clin Radiol, D-81377 Munich, Germany

[24] Ist Giannina Gaslini, Dept Pediat Neuroradiol, I-16147 Genoa, Italy

[25] Univ Kiel, Inst Human Genet, Campus Kiel, D-24105 Kiel, Germany

[26] Univ Hosp Schleswig Holstein, Campus Kiel, D-24105 Kiel, Germany

[27] Ulm Univ, Inst Human Genet, D-89081 Ulm, Germany

[28] Ulm Univ, Med Ctr, D-89081 Ulm, Germany

[29] Ludwig Maximilians Univ Munchen, Inst Pathol, D-81377 Munich, Germany

[30] Johns Hopkins Univ, Div Neuropathol, Baltimore, MD 21287 USA

[31] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA

[32] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8S 4L8, Canada

[33] Univ Hosp Heidelberg, Dept Pediat Hematol & Oncol, D-69120 Heidelberg, Germany

[34] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[35] Univ Med Ctr, Dept Pediat Hematol & Oncol, D-20246 Hamburg, Germany

来源：

DEVELOPMENTAL CELL | 2018年 / 44卷 / 06期

关键词：

CEREBELLAR DEVELOPMENT; MOUSE MODEL; CBP GENE; EXPRESSION; MICE; MIGRATION; ACTIVATION; PROLIFERATION; LOCALIZATION; SUBGROUPS;

D O I：

10.1016/j.devcel.2018.02.012

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：709 / +

页数：22

共 64 条

[1] Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site [J].

Ågren, M ;

Kogerman, P ;

Kleman, MI ;

Wessling, M ;

Toftgård, R .

GENE, 2004, 330 :101-114

[2] The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis [J].

Aguado, Tania ;

Romero, Eva ;

Monory, Krisztina ;

Palazuelos, Javier ;

Sendtner, Michael ;

Marsicano, Giovanni ;

Lutz, Beat ;

Guzman, Manuel ;

Galve-Roperh, Ismael .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (33) :23892-23898

[3] Mouse and rat BDNF gene structure and expression revisited [J].

Aid, Tamara ;

Kazantseva, Anna ;

Piirsoo, Marko ;

Palm, Kaia ;

Timmusk, Tonis .

JOURNAL OF NEUROSCIENCE RESEARCH, 2007, 85 (03) :525-535

[4] Tyrosine kinase B receptor and BDNF expression in ovarian cancers - Effect on cell migration, angiogenesis and clinical outcome [J].

Au, Christy W. H. ;

Siu, Michelle K. Y. ;

Liao, Xiaoyun ;

Wong, Esther S. Y. ;

Ngan, Hextan Y. S. ;

Tam, Kar Fai ;

Chan, Dominic C. W. ;

Chan, Queeny K. Y. ;

Cheung, Annie N. Y. .

CANCER LETTERS, 2009, 281 (02) :151-161

[5] MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors [J].

Berenguer, Jordi ;

Herrera, Antonio ;

Vuolo, Laura ;

Torroba, Blanca ;

Llorens, Franc ;

Sumoy, Lauro ;

Pons, Sebastian .

MOLECULAR AND CELLULAR BIOLOGY, 2013, 33 (14) :2706-2717

[6] UNUSUAL ASSOCIATION - DANDY-WALKER-LIKE MALFORMATION IN THE RUBINSTEIN-TAYBI SYNDROME [J].

BONIOLI, E ;

BELLINI, C ;

DISTEFANO, A .

AMERICAN JOURNAL OF MEDICAL GENETICS, 1989, 33 (03) :420-421

[7]

Borghesani PR, 2002, DEVELOPMENT, V129, P1435

[8] Rubinstein-Taybi Syndrome Predisposing to Non-WNT, Non-SHH, Group 3 Medulloblastoma [J].

Bourdeaut, Franck ;

Miquel, Catherine ;

Richer, Wilfrid ;

Grill, Jacques ;

Zerah, Michel ;

Grison, Camille ;

Pierron, Gaelle ;

Amiel, Jeanne ;

Krucker, Clementine ;

Radvanyi, Francois ;

Brugieres, Laurence ;

Delattre, Olivier .

PEDIATRIC BLOOD & CANCER, 2014, 61 (02) :383-386

[9] CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's disease [J].

Caccamo, Antonella ;

Maldonado, Monica A. ;

Bokov, Alex F. ;

Majumder, Smita ;

Oddo, Salvatore .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (52) :22687-22692

[10] Identification of a low-molecular weight TrkB antagonist with anxiolytic and antidepressant activity in mice [J].

Cazorla, Maxime ;

Premont, Joel ;

Mann, Andre ;

Girard, Nicolas ;

Kellendonk, Christoph ;

Rognan, Didier .

JOURNAL OF CLINICAL INVESTIGATION, 2011, 121 (05) :1846-1857

← 1 2 3 4 5 6 7 →