Disruption of cerebral cortex MET signaling in autism spectrum disorder.
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.


CONCLUSIONS
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.
Campbell
Daniel B
DB
Department of Pharmacology, Vanderbilt University, Nashville, TN 37203, USA.
D'Oronzio
Rosanna
R
Garbett
Krassi
K
Ebert
Philip J
PJ
Mirnics
Karoly
K
Levitt
Pat
P
Persico
Antonio M
AM
D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology*; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000503:physiopathology*; D002648:Child; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D008297:Male; D009415:Nerve Net / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D017978:Receptors, Growth Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013702:Temporal Lobe / Q000737:chemistry; D014015:Tissue Banks; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D017228:Hepatocyte Growth Factor; D004247:DNA; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases