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Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.
Pubmed ID: 25757017
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The Canadian Institutes of Health Research (CIHR) is the Government of Canada''s agency responsible for funding health research in Canada. CIHR was created in 2000 under the authority of the CIHR Act and reports to Parliament through the Minister of Health. CIHR''s budget for 2008-09 is $928.6 million, of which $132 million is allocated to administering the Networks of Centres of Excellence and Canada Research Chair programs. CIHR was created to transform health research in Canada by: * funding more research on targeted priority areas; * building research capacity in under-developed areas such as population health and health services research; * training the next generation of health researchers; and * focusing on knowledge translation, so that the results of research are transformed into policies, practices, procedures, products and services. CIHR consists of 13 virtual institutes, a structure that is unique in the world. These innovative institutes bring together all partners in the research process - the people who fund research, those who carry it out and those who use its results - to share ideas and focus on what Canadians need: good health and the means to prevent disease and fight it when it happens. Each institute supports a broad spectrum of research in its topic areas and, in consultation with its stakeholders, sets priorities for research in those areas.
View all literature mentionsCenter that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine function of every gene in mouse genome. These mice will be preserved in repositories and made available to scientific community representing valuable resource for basic scientific research as well as generating new models for human diseases.
View all literature mentionsMus musculus with name B6.129S2-Emx1tm1(cre)Krj/J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionslaboratory mouse with name CD-1 x C57BL/6J from MGI.
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