title: The autism risk genes MET and PLAUR differentially impact cortical development.
abstract: Candidate risk genes for autism spectrum disorder (ASD) have been identified, but the challenge of determining their contribution to pathogenesis remains. We previously identified two ASD risk genes encoding the receptor tyrosine kinase MET and the urokinase plasminogen activator receptor (PLAUR), which is thought to modulate availability of the MET ligand. We also reported a role for Met signaling in cortical interneuron development in vitro and a reduction of these neurons in uPAR (mouse ortholog of PLAUR) null mice, suggesting that disruption of either gene impacts cortical development similarly. Here, we modify this conclusion, reporting that interneuron numbers are unchanged in the neocortex of Met(fx/fx) / Dlx5/6(cre) mice, in which Met is ablated from cells arising from the ventral telencephalon (VTel). Consistent with this, Met transcript is not detected in the VTel during interneuron genesis and migration; furthermore, during the postnatal period of interneuron maturation, Met is co-expressed in glutamatergic projection neurons, but not interneurons. Low levels of Met protein are expressed in the VTel at E12.5 and E14.5, likely reflecting the arrival of Met containing corticofugal axons. Met expression, however, is induced in E12.5 VTel cells after 2 days in vitro, perhaps underlying discrepancies between observations in vitro and in Met(fx/fx) / Dlx5/6(cre) mice. We suggest that, in vivo, Met impacts the development of cortical projection neurons, whereas uPAR influences interneuron maturation. An altered balance between excitation and inhibition has been postulated as a biological mechanism for ASD; this imbalance could arise from different risk genes differentially affecting either or both elements.
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine at USC, Los Angeles, California 90033, USA. keagleso@usc.edu
authors.forename: Kathie L
authors.initials: KL
authors.lastname: Eagleson
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Campbell
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Thompson
authors.forename: Mica Y
authors.initials: MY
authors.lastname: Bergman
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
mesh_terms: D000483:Alleles; D000818:Animals; D002452:Cell Count; D002465:Cell Movement / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology*; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D015870:Gene Expression / Q000235:genetics; D056726:Genetic Association Studies; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D007395:Interneurons / Q000473:pathology / Q000502:physiology; D054220:Malformations of Cortical Development / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: C524899:Plaur protein, mouse; D055293:Receptors, Urokinase Plasminogen Activator; D019859:Proto-Oncogene Proteins c-met