The speech vocalization gene, FoxP2, regulates interneuron fate decisions
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1
University of Toronto, Developmental and Stem Cell Biology, Canada
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2
Mount Sinai School of Medicine, Department of Psychiatry, Seaver Autism Center, United States
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3
University of Toronto, Cell Biology, MaRS Center, Hospital for Sick Children, Canada
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4
University of Toronto, Departments of Molecular Genetics and Physiology, Canada
The transcription factor FoxP2 is expressed in the developing brain and is involved in speech development and susceptibility to autism. To determine the role of FoxP2 in the developing brain, we focused upon the developing cerebral cortex. Immunocytochemistry demonstrated that FoxP2 is expressed in a subset of nestin-positive precursors, and in newly born interneurons in both the cortex and the ganglionic eminence. In utero electroporation revealed that only a small subset of these cortical interneurons were generated from cortical precursors, consistent with the fact that most cortical interneurons migrate into the cortex from the ganglionic eminence. To ask about the potential role of FoxP2 in these cells, we ectopically-expressed FoxP2 in E12 cortical precursor cultures and E13/14 cortical precursors in vivo. In both cases, FoxP2 expression was sufficient to enhance the number of neurons expressing interneuron markers. Thus, FoxP2 is sufficient to promote interneuron genesis from precursors that normally make small numbers of interneurons. To ask if FoxP2 is also necessary for genesis of interneurons, we cultured E12 precursors from the medial ganglionic eminence (MGE), where approximately 40% of the precursors express FoxP2. ShRNA-mediated knockdown of FoxP2 in these cultures and MGE precursors in vivo decreased the number of interneurons generated. Thus, FoxP2 is also necessary for genesis of at least some MGE interneurons, raising the possibility that it might transcriptionally activate genes necessary for the interneuron phenotype, such as Dlx transcription factors. Consistent with this hypothesis, chromatin immunoprecipitation assays demonstrated that FoxP2 is associated with the Dlx-1 promoter in the embryonic brain, and heterologous cotransfection assays demonstrated that FoxP2 could transcriptionally activate the Dlx-1 promoter. Together these studies suggest that FoxP2 is essential for the normal genesis of cortical interneurons, and that perturbations in this activity might underlie the behavioral deficits in vocalization seen in individuals with FoxP2 mutations.
Acknowledgements: This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to F.D.M. and D.R.K. I.C.G.W. was initially supported by a Restracomp Postdoctoral Research Fellowship from the Hospital for Sick Children Foundation and presently by a Postdoctoral Research Fellowship from the CIHR.
Conference:
B.R.A.I.N. platform in Physiology poster day 2009, Toronto, ON, Canada, 16 Dec - 16 Dec, 2009.
Presentation Type:
Poster Presentation
Topic:
Poster presentations
Citation:
Weaver
IC,
Sakurai
T,
Buxbaum
JD,
Kaplan
DR and
Miller
FD
(2009). The speech vocalization gene, FoxP2, regulates interneuron fate decisions.
Front. Neurosci.
Conference Abstract:
B.R.A.I.N. platform in Physiology poster day 2009.
doi: 10.3389/conf.neuro.03.2009.17.058
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Received:
18 Dec 2009;
Published Online:
18 Dec 2009.
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Correspondence:
Ian C Weaver, University of Toronto, Developmental and Stem Cell Biology, Toronto, Canada, ianweaver01@hotmail.com