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

doi:10.1016/j.celrep.2017.11.018

Control of Huntington's Disease-Associated Phenotypes by the Striatum-Enriched Transcription Factor Foxp2

Cell Rep. 2017 Dec 5;21(10):2688-2695. doi: 10.1016/j.celrep.2017.11.018.

Authors

Affiliations

¹ 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.
² Center for Neuroscience and Cell Biology (CNC) and Faculty of Pharmacy, The University of Coimbra Rua Larga, 3004-504 Coimbra, Portugal.
³ Picower Institute for Learning and Memory, Cambridge, MA 02139, USA.
⁴ Picower Institute for Learning and Memory, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Bioinformatics, Boston University, Boston, MA 02215, USA.
⁶ ICM (Brain and Spine Institute) Pitié-Salpêtrière Hospital, CNRS UMR 7225, 75013 Paris, France.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Program in Bioinformatics, Boston University, Boston, MA 02215, USA; Department of Mathematics and Statistics, Boston University, Boston, MA 02215, USA.
⁹ 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. Electronic address: mheiman@mit.edu.

PMID: 29212017
DOI: 10.1016/j.celrep.2017.11.018

Abstract

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.

Keywords: Foxp2; Huntington’s disease; corticostriatal synapse; striatum.

MeSH terms

Animals
Blotting, Western
Corpus Striatum / metabolism*
Disease Models, Animal
Fluorescent Antibody Technique, Indirect
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism*
Gene Expression Regulation / genetics
Gene Expression Regulation / physiology
Humans
Huntington Disease / genetics
Huntington Disease / metabolism*
Male
Mice
Phenotype
Repressor Proteins / genetics
Repressor Proteins / metabolism*

Substances

Forkhead Transcription Factors
Foxp2 protein, mouse
Repressor Proteins