title: Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk.
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 of MET to ASD pathogenesis, we examined the expression and transcriptional regulation of MET by 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 of MET expression is highly complementary to the expression pattern of FOXP2, suggesting the latter may play 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.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Mukamel
authors.forename: Genevieve
authors.initials: G
authors.lastname: Konopka
authors.forename: Eric
authors.initials: E
authors.lastname: Wexler
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Osborn
authors.forename: Hongmei
authors.initials: H
authors.lastname: Dong
authors.forename: Mica Y
authors.initials: MY
authors.lastname: Bergman
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D012307:Risk Factors
chemical_list: D020121:5' Untranslated Regions; C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met