Control of Huntington’s Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2
Lea J. Hachigian,
Vitor Carmona,
Robert J. Fenster,
Ruth Kulicke,
Adrian Heilbut,
Annie Sittler,
Luís Pereira de Almeida,
Jill P. Mesirov,
Fan Gao,
Eric D. Kolaczyk,
Myriam Heiman
Affiliations
Lea J. Hachigian
Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Vitor Carmona
Center for Neuroscience and Cell Biology (CNC) and Faculty of Pharmacy, The University of Coimbra Rua Larga, 3004-504 Coimbra, Portugal
Robert J. Fenster
Picower Institute for Learning and Memory, Cambridge, MA 02139, USA
Ruth Kulicke
Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Adrian Heilbut
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Bioinformatics, Boston University, Boston, MA 02215, USA
Annie Sittler
ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, CNRS UMR 7225, 75013 Paris, France
Luís Pereira de Almeida
Center for Neuroscience and Cell Biology (CNC) and Faculty of Pharmacy, The University of Coimbra Rua Larga, 3004-504 Coimbra, Portugal
Jill P. Mesirov
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Fan Gao
Picower Institute for Learning and Memory, Cambridge, MA 02139, USA
Eric D. Kolaczyk
Program in Bioinformatics, Boston University, Boston, MA 02215, USA; Department of Mathematics and Statistics, Boston University, Boston, MA 02215, USA
Myriam Heiman
Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Corresponding author
Summary: Alteration of corticostriatal glutamatergic function is an early pathophysiological change associated with Huntington’s disease (HD). The factors that regulate the maintenance of corticostriatal glutamatergic synapses post-developmentally are not well understood. Recently, the striatum-enriched transcription factor Foxp2 was implicated in the development of these synapses. Here, we show that, in mice, overexpression of Foxp2 in the adult striatum of two models of HD leads to rescue of HD-associated behaviors, while knockdown of Foxp2 in wild-type mice leads to development of HD-associated behaviors. We note that Foxp2 encodes the longest polyglutamine repeat protein in the human reference genome, and we show that it can be sequestered into aggregates with polyglutamine-expanded mutant Huntingtin protein (mHTT). Foxp2 overexpression in HD model mice leads to altered expression of several genes associated with synaptic function, genes that present additional targets for normalization of corticostriatal dysfunction in HD. : Hachigian et al. demonstrate that manipulating levels of the striatum-enriched transcription factor Foxp2 can either rescue or mimic HD-associated behaviors in vivo. They link Foxp2 to the post-developmental regulation of the structure and function of the corticostriatal synapse. Keywords: Huntington’s disease, Foxp2, striatum, corticostriatal synapse
