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Dev Cell. 2018 Mar 26;44(6):709-724.e6. doi: 10.1016/j.devcel.2018.02.012. Epub 2018 Mar 15.

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

Author information

1
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany; Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Neurobiology, Harvard Medical School, Boston, MA 02215, USA.
2
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany.
3
Munich Center for Integrated Protein Science at the Chemistry Department, Technical University, 85747 Munich, Germany.
4
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
5
Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada.
6
Research Institute Children's Cancer Center Hamburg, Martinistrasse 52, N63 (HPI), Hamburg 20251, Germany.
7
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany; Department of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany.
8
German Center for Neurodegenerative Diseases (DZNE), Ludwig-Maximilians-University, 81377 Munich, Germany.
9
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany; Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-University, 80337 Munich, Germany.
10
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
11
Microarray and Deep-Sequencing Core Facility, University Medical Center Göttingen, 37077 Göttingen, Germany.
12
Institute for Clinical Neurobiology, University of Würzburg, 97078 Würzburg, Germany.
13
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany; Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany.
14
Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-University, 81377 Munich, Germany.
15
Department of Translational Genomics, University of Cologne, 50931 Cologne, Germany.
16
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
17
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC VSZ 4S6, Canada.
18
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128 Mainz, Germany.
19
Institute of Clinical Radiology, Ludwig-Maximilians-University, 81377 Munich, Germany.
20
Department of Pediatric Neuroradiology, Istituto Giannina Gaslini, 16147 Genova, Italy.
21
Institute of Human Genetics, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Institute for Human Genetics, Ulm University and Ulm University Medical Center, 89081 Ulm, Germany.
22
Institute of Pathology, Ludwig-Maximilians-University, 81377 Munich, Germany.
23
Division of Neuropathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
24
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada.
25
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany; Department of Pediatric Hematology and Oncology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
26
Arthur and Sonia Labatt Brain Tumour Research Centre and Division of Neurosurgery, Hospital for Sick Children (HSC), Toronto, ON M5G 1L7, Canada; Program in Developmental and Stem Cell Biology, HSC, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
27
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), Core Center Heidelberg, 69120 Heidelberg, Germany.
28
Center for Neuropathology, Ludwig-Maximilians-University, 81377 Munich, Germany; Research Institute Children's Cancer Center Hamburg, Martinistrasse 52, N63 (HPI), Hamburg 20251, Germany; Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: u.schueller@uke.de.

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:

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

PMID:
29551561
DOI:
10.1016/j.devcel.2018.02.012
[Indexed for MEDLINE]
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