Disruption of cerebral cortex MET signaling in autism spectrum disorder.

Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, Persico AM
Ann Neurol. 2007 62 (3): 243-50

PMID: 17696172 · DOI:10.1002/ana.21180

OBJECTIVE - Multiple genes contribute to autism spectrum disorder (ASD) susceptibility. One particularly promising candidate is the MET gene, which encodes a receptor tyrosine kinase that mediates hepatocyte growth factor (HGF) signaling in brain circuit formation, immune function, and gastrointestinal repair. The MET promoter variant rs1858830 allele "C" is strongly associated with ASD and results in reduced gene transcription. Here we examined expression levels of MET and members of the MET signaling pathway in postmortem cerebral cortex from ASD cases and healthy control subjects.

METHODS - Protein, total RNA, and DNA were extracted from postmortem temporal cortex gray matter samples (BA 41/42, 52, or 22) belonging to eight pairs of ASD cases and matched control subjects. MET protein expression was determined by Western blotting; messenger RNA expression of MET and other related transcripts was assayed by microarray and quantitative reverse transcriptase polymerase chain reaction.

RESULTS - MET protein levels were significantly decreased in ASD cases compared with control subjects. This was accompanied in ASD brains by increased messenger RNA expression for proteins involved in regulating MET signaling activity. Analyses of coexpression of MET and HGF demonstrated a positive correlation in control subjects that was disrupted in ASD cases.

INTERPRETATION - Altered expression of MET and related molecules suggests dysregulation of signaling that may contribute to altered circuit formation and function in ASD. The complement of genes that encode proteins involved in MET activation appears to undergo long-term compensatory changes in expression that may be a hallmark contribution to the pathophysiology of ASD.

MeSH Terms (23)

Autistic Disorder Blotting, Western Cerebral Cortex Child Databases, Factual DNA Female Genotype Hepatocyte Growth Factor Humans Male Nerve Net Oligonucleotide Array Sequence Analysis Proto-Oncogene Proteins Proto-Oncogene Proteins c-met Receptor Protein-Tyrosine Kinases Receptors, Growth Factor Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Temporal Lobe Tissue Banks Transcription, Genetic

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