title: Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain.
abstract: Forkhead-box protein P2 is a transcription factor that has been associated with intriguing aspects of cognitive function in humans, non-human mammals, and song-learning birds. Heterozygous mutations of the human FOXP2 gene cause a monogenic speech and language disorder. Reduced functional dosage of the mouse version (Foxp2) causes deficient cortico-striatal synaptic plasticity and impairs motor-skill learning. Moreover, the songbird orthologue appears critically important for vocal learning. Across diverse vertebrate species, this well-conserved transcription factor is highly expressed in the developing and adult central nervous system. Very little is known about the mechanisms regulated by Foxp2 during brain development. We used an integrated functional genomics strategy to robustly define Foxp2-dependent pathways, both direct and indirect targets, in the embryonic brain. Specifically, we performed genome-wide in vivo ChIP-chip screens for Foxp2-binding and thereby identified a set of 264 high-confidence neural targets under strict, empirically derived significance thresholds. The findings, coupled to expression profiling and in situ hybridization of brain tissue from wild-type and mutant mouse embryos, strongly highlighted gene networks linked to neurite development. We followed up our genomics data with functional experiments, showing that Foxp2 impacts on neurite outgrowth in primary neurons and in neuronal cell models. Our data indicate that Foxp2 modulates neuronal network formation, by directly and indirectly regulating mRNAs involved in the development and plasticity of neuronal connections.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Vernes
authors.forename: Peter L
authors.initials: PL
authors.lastname: Oliver
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spiteri
authors.forename: Helen E
authors.initials: HE
authors.lastname: Lockstone
authors.forename: Rathi
authors.initials: R
authors.lastname: Puliyadi
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Joses
authors.initials: J
authors.lastname: Ho
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.forename: Ariel
authors.initials: A
authors.lastname: Brewer
authors.forename: Ernesto
authors.initials: E
authors.lastname: Lowy
authors.forename: Jérôme
authors.initials: J
authors.lastname: Nicod
authors.forename: Matthias
authors.initials: M
authors.lastname: Groszer
authors.forename: Dilair
authors.initials: D
authors.lastname: Baban
authors.forename: Natasha
authors.initials: N
authors.lastname: Sahgal
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003342:Corpus Striatum / Q000254:growth & development; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009154:Mutation; D016501:Neurites / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D051858:Forkhead Transcription Factors; C432918:Foxp2 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins