A new synaptic player leading to autism risk: Met receptor tyrosine kinase

Abstract

The validity for assigning disorder risk to an autism spectrum disorder (ASD) candidate gene comes from convergent genetic, clinical, and developmental neurobiology data. Here, we review these lines of evidence from multiple human genetic studies, and non-human primate and mouse experiments that support the conclusion that the MET receptor tyrosine kinase (RTK) functions to influence synapse development in circuits relevant to certain core behavioral domains of ASD. There is association of both common functional alleles and rare copy number variants that impact levels of MET expression in the human cortex. The timing of Met expression is linked to axon terminal outgrowth and synaptogenesis in the developing rodent and primate forebrain, and both in vitro and in vivo studies implicate this RTK in dendritic branching, spine maturation, and excitatory connectivity in the neocortex. This impact can occur in a cell-nonautonomous fashion, emphasizing the unique role that Met plays in specific circuits relevant to ASD.

Fig. 1

Diagram illustrating the three allelic variants of the gene encoding the MET receptor tyrosine kinase (MET) that have been associated with an increased risk for ASD in multiple independent studies. In addition, rare copy number variants (CNVs) that interrupt the MET gene have been associated with ASD. See reference list for citations noted in the figure

Fig. 2

Summary of MET/Met expression in the developing primate and mouse forebrain. Green shading indicates immunolocalization of the receptor protein in cortical and Subcortical regions and axon tracts. Regions denoted do not express the Met transcript (based on analyses in the mouse), but have detectable protein because each structure receives Met-immunoreactive axons. See (Judson et al. ; Judson et al. 2011) for more details

Fig. 3

Conditional Met deletion by Emx1^Cre (−/−) increases proximal and reduces distal apical dendritic branching of neocortical pyramidal neurons in post-pubertal animals. The overall impact results in a reduced volume of cortical tissue sampled by the apical dendrites. Analysis of spine number and size on basal dendrites revealed an approximately 22% increase in spine head volume, but no change in density of spines. See (Judson et al. 2010) for details