Regulation of MET by FOXP2, Genes Implicated in Higher Cognitive Dysfunction and Autism Risk
| Autor: | Genevieve Konopka, Mica Y. Bergman, Pat Levitt, Eric M. Wexler, Gregory E. Osborn, Zohar Mukamel, Hongmei Dong, Daniel H. Geschwind |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Biology Article Risk Factors Gene expression Transcriptional regulation medicine Humans Receptors Growth Factor Autistic Disorder Transcription factor Psychological repression Gene Temporal cortex Genetics General Neuroscience Infant Newborn Gene Expression Regulation Developmental FOXP2 Forkhead Transcription Factors Proto-Oncogene Proteins c-met medicine.anatomical_structure Cerebral cortex Child Development Disorders Pervasive Female 5' Untranslated Regions Cognition Disorders Neuroscience |
| Popis: | 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 disruptsMETgene 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.METmRNA 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 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 regulatesMET. Indeed, FOXP2 binds directly to the 5′ regulatory region ofMET, and overexpression of FOXP2 results in transcriptional repression ofMET. The expression ofMETin restricted human neocortical regions, and its regulation in part by FOXP2, is consistent with genetic evidence forMETcontributing to ASD risk. |
| Databáze: | OpenAIRE |
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