Foxp2 regulates gene networks implicated in neurite outgrowth in the developing brain

Sonja C Vernes, Peter L Oliver, Elizabeth Spiteri, Helen E Lockstone, Rathi Puliyadi, Jennifer M Taylor, Joses Ho, Cedric Mombereau, Ariel Brewer, Ernesto Lowy, Jérôme Nicod, Matthias Groszer, Dilair Baban, Natasha Sahgal, Jean-Baptiste Cazier, Jiannis Ragoussis, Kay E Davies, Daniel H Geschwind, Simon E Fisher

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)e1002145
JournalPLoS Genetics
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 2011

Keywords

  • Animals
  • Brain/embryology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Corpus Striatum/growth & development
  • Forkhead Transcription Factors/genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks
  • Mice
  • Mice, Inbred C57BL
  • Models, Biological
  • Mutation
  • Neurites/metabolism
  • Oligonucleotide Array Sequence Analysis/methods
  • Primary Cell Culture
  • RNA, Messenger/genetics
  • Repressor Proteins/genetics

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