title: CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.
abstract: The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Institute for Medical Sciences, University of Toronto, Toronto, Canada M5G 1X5.
authors.forename: David
authors.initials: D
authors.lastname: Tsui
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Voronova
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7.
authors.forename: Denis
authors.initials: D
authors.lastname: Gallagher
authors.affiliation: Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Institute for Medical Sciences, University of Toronto, Toronto, Canada M5G 1X5; Department of Molecular Genetics, University of Toronto, Toronto, Canada M5G 1X5.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Institute for Medical Sciences, University of Toronto, Toronto, Canada M5G 1X5; Department of Molecular Genetics, University of Toronto, Toronto, Canada M5G 1X5; Department of Physiology, University of Toronto, Toronto, Canada M5G 1X5. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.affiliation: Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7; Cell Biology, Hospital for Sick Children, Toronto, Canada M5G 1L7. Electronic address: jiwang@toh.on.ca.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D057895:Haploinsufficiency; D007395:Interneurons / Q000166:cytology*; D051379:Mice; D016133:Polymerase Chain Reaction; D016548:Prosencephalon / Q000166:cytology* / Q000196:embryology; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D050880:p300-CBP Transcription Factors
keywords: CBP; Cortical development; Epilepsy; Ganglionic eminence; Interneuron; Neural stem cell; Neurogenesis; Rubinstein–Taybi syndrome