Research Highlight:

MET: A Link to Autism and GI Disorders

Original Research Article:
MC Judson, MY Bergman, DB Campbell, KL Eagleson and P Levitt (2009). Dynamic Gene and Protein Expression Patterns of the Autism-Associated Met Receptor Tyrosine Kinase in the Developing Mouse Forebrain. J Comp Neurol. 513: 511-531.

Characterizing and understanding autism spectrum disorders (ASD) represent great challenges facing neuroscientists today. Accumulating evidence suggests that alterations in the patterning of specific brain structures and circuitry during development may contribute to ASD. The Met tyrosine kinase receptor is important for cell differentiation and organ development. In the developing CNS, Met is thought to facilitate a number of processes including neuronal migration, axon guidance and dendritic arborization by mediating cellular responses to its endogenous ligand, hepatocyte growth factor (HGF). In a paper recently published in The Journal of Comparative Neurology, Judson and colleagues followed up on previous reports relating autism susceptibility to alterations in Met signaling by characterizing Met expression patterns in the developing mouse brain.

The authors used in situ hybridization and immunohistochemistry to localize Met transcript and protein, respectively, within the developing murine forebrain. They showed that Met is primarily expressed in specific cortical projection neurons and in certain limbic system components, and that the protein localizes to axonal projections and is particularly enriched in major axon tracts such as the corpus callosum. In addition to characterizing the spatial expression pattern, the temporal pattern of developmental expression was analyzed by quantitative western blot. They found evidence that Met expression levels are highest in the early postnatal developmental period from P0 to P21. This corresponds to the time of mouse brain development in which neurite outgrowth and synaptogenesis occur. This finding further supports a role for Met in the formation of neural circuitry, possibly by facilitating outgrowth and path-finding in forebrain axons. Using an Emx1cre line and a “floxed” Met allele, the authors analyzed mice with a selective ablation of Met in all cells arising from dorsal pallium, which includes projection neurons of the cerebral cortex, hippocampus and some amygdaloid nuclei. This analysis was useful for determining the source of Met expression in the forebrain and further supported the hypothesis that Met is most highly expressed in the axonal projections of neurons, particularly projection neurons of the cortex and components of limbic circuitry.

The highest levels of Met expression were observed in the cerebral cortex, and in limbic system associated structures thought to be important for emotional and social function, implicating Met in the establishment and organization of the neural circuitry responsible for maintaining normal emotional and social function. The manifestation of ASD often involves abnormal emotional and social behavior, possibly resulting from a physical disorganization of the circuits involved. This study provides evidence for a potential molecular substrate contributing to developmental abnormalities associated with ASD. Furthermore, it implies a significant role for Met receptor related signaling in normal development of the limbic system and forebrain.