Expression and Transcriptional Regulation of the ASD-Associated Met Receptor Tyrosine Kinase During Mammalian Forebrain Development

Abstract

The Met receptor tyrosine kinase is capable of mediating several neurodevelopmental events in vitro, but its functions in vivo are incompletely understood. Three alleles in the 5’ regulatory region of the human ortholog, MET, increase the risk for autism spectrum disorder, suggesting that disruptions in Met expression may contribute to the aberrant circuit development characteristic of neurodevelopmental disorders. To gain insight into the functional roles for Met in vivo, we mapped Met transcript and protein expression throughout perinatal and postanatal development. This study revealed complex and dynamic spatiotemporal patterns of expression, suggesting a role for the receptor in neurite outgrowth and synaptogenesis, particularly in establishing connectivity in forebrain circuits relevant to the social and emotional dimensions of behavior. The complement of transcription factors controlling Met expression in the nervous system is poorly understood. Yet knowledge of these regulatory factors is critical to understanding how Met expression patterns are established in vivo, and gives insight into sources of vulnerability to disrupted expression and consequent aberrations in circuit patterning. Previous work has demonstrated that the ASD-associated MET allele alters Sp-family binding to the gene’s 5’ regulatory region. In this study, we demonstrate that Sp4 in particular has a role in regulating Met expression in the mammalian forebrain. Further, we developed a mass-spectrometric-based screen to identify additional regulators of Met expression, and used this screen to identify 49 putative regulators from postnatal day 7 mouse cortical tissue. A novel bioinformatics approach provides new opportunities for determining the downstream targets of regulatory genes relevant to autism risk.