The autism risk genes MET and PLAUR differentially impact cortical development
- 3 December 2010
- journal article
- research article
- Published by Wiley in Autism Research
- Vol. 4 (1), 68-83
- https://doi.org/10.1002/aur.172
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 Metfx/fx/ Dlx5/6cre 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 Metfx/fx/ Dlx5/6cre 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.Keywords
This publication has 108 references indexed in Scilit:
- Evidence of cell‐nonautonomous changes in dendrite and dendritic spine morphology in the met‐signaling–deficient mouse forebrainJournal of Comparative Neurology, 2010
- Specificity of prenatal cocaine exposure effects on cortical interneurons is independent from dopamine D1 receptor co-localizationJournal of Chemical Neuroanatomy, 2010
- Genetic advances in autism: heterogeneity and convergence on shared pathwaysCurrent Opinion in Genetics & Development, 2009
- Dynamic gene and protein expression patterns of the autism‐associated met receptor tyrosine kinase in the developing mouse forebrainJournal of Comparative Neurology, 2009
- Regulation of Cerebral Cortical Size and Neuron Number by Fibroblast Growth Factors: Implications for AutismJournal of Autism and Developmental Disorders, 2008
- Prenatal stress and risk for autismNeuroscience & Biobehavioral Reviews, 2008
- Genetic evidence implicating multiple genes in the MET receptor tyrosine kinase pathway in autism spectrum disorderAutism Research, 2008
- Structural Variation of Chromosomes in Autism Spectrum DisorderAmerican Journal of Human Genetics, 2008
- The New Neurobiology of AutismArchives of Neurology, 2007
- Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a reviewEuropean Journal of Pediatrics, 2007