TY - JOUR
T1 - Regulation of MET by FOXP2, genes implicated in higher cognitive dysfunction and autism risk
AU - Mukame, Zohar
AU - Konopka, Genevieve
AU - Wexler, Eric
AU - Osborn, Gregory E.
AU - Dong, Hongmei
AU - Bergman, Mica Y.
AU - Levitt, Pat
AU - Geschwind, Daniel H.
PY - 2011/8/10
Y1 - 2011/8/10
N2 - 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.
AB - 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.
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U2 - 10.1523/JNEUROSCI.0181-11.2011
DO - 10.1523/JNEUROSCI.0181-11.2011
M3 - Article
C2 - 21832174
AN - SCOPUS:80051569371
SN - 0270-6474
VL - 31
SP - 11437
EP - 11442
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 32
ER -