Recent research has suggested that organization of neural circuitry may be altered in autism spectrum disorders (ASD). Hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, are involved in the development of the forebrain, and MET has been identified as a susceptibility loci for autism. In neural tissue, HGF/SF binding to Met induces a signaling cascade that can influence cell migration, proliferation, and formation of neurite processes.
HGF/SF and Met are known to be expressed in the developing telencephalon, and changes in HGF/SF or Met expression appear to alter proliferation and formation of processes in neurons. This study employed mutant mice with a targeted mutation of Met in the cerebral cortex to examine how changes in HGF/SF-Met signaling could lead to alterations in neural circuitry.
Methods: This study employed transgenic mice with a targeted signaling mutant of Met in the cerebral cortex, along with immunohistochemical, biochemical and anatomical techniques to examine the effects of HGF-Met signaling on neural development.
Results: Mice lacking normal Met expression in the cerebral cortex show alterations in several aspects of cortical structure. Reduced HGF/SF-Met signaling in these mice leads to alterations in the laminar structure of the cortex. We also found alterations in cell proliferation in the developing cortex, as well as changes in pyramidal cell dendritic structure, which may contribute to the alterations in laminar structure.
Conclusions: Our data suggest that Met signaling is required in the mouse forebrain for proper cortical lamination, neuronal proliferation, and formation of processes. These alterations could disrupt the formation of neuronal circuitry. Such disruptions can lead to profound neurological and behavioral consequences such as those portrayed in ASD.