Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk

Zohar Mukame, Genevieve Konopka, Eric Wexler, Gregory E. Osborn, Hongmei Dong, Mica Y. Bergman, Pat Levitt, Daniel H. Geschwind

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Autism spectrum disorder (ASD) is a highly heritable, behaviorally defined, heterogeneous disorder of unknown pathogenesis. Several genetic risk genes have been identified, including the gene encoding the receptor tyrosine kinase MET, which regulates neuronal differentiation and growth. An ASD-associated polymorphism disrupts MET gene transcription, and there are reduced levels of MET protein expression in the mature temporal cortex of subjects with ASD. To address the possible neurodevelopmental contribution ofMETto ASD pathogenesis, we examined the expression and transcriptional regulation ofMETby a transcription factor, FOXP2, which is implicated in regulation of cognition and language, two functions altered in ASD. MET mRNA expression in the midgestation human fetal cerebral cortex is strikingly restricted, localized to portions of the temporal and occipital lobes. Within the cortical plate of the temporal lobe, the pattern ofMETexpression is highly complementary to the expression pattern of FOXP2, suggesting the lattermayplay a role in repression of gene expression. Consistent with this, MET and FOXP2 also are reciprocally expressed by differentiating normal human neuronal progenitor cells (NHNPs) in vitro, leading us to assess whether FOXP2 transcriptionally regulates MET. Indeed, FOXP2 binds directly to the 5' regulatory region of MET, and overexpression of FOXP2 results in transcriptional repression of MET. The expression of MET in restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence for MET contributing to ASD risk.

Original languageEnglish (US)
Pages (from-to)11437-11442
Number of pages6
JournalJournal of Neuroscience
Volume31
Issue number32
DOIs
StatePublished - Aug 10 2011

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk'. Together they form a unique fingerprint.

  • Cite this

    Mukame, Z., Konopka, G., Wexler, E., Osborn, G. E., Dong, H., Bergman, M. Y., Levitt, P., & Geschwind, D. H. (2011). Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk. Journal of Neuroscience, 31(32), 11437-11442. https://doi.org/10.1523/JNEUROSCI.0181-11.2011