Fine-Tuning the Mouse Forebrain by HGF/SF-Met Signaling

Background:  Integrating activity across various brain regions is critical for supporting adaptive behavior.  Recent research has suggested that organization of neural circuitry may be affected in autism. The hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, have been genetically linked as autism susceptibility loci and further implicated in the development of the mouse forebrain.  HGF/SF, when bound to Met, induces a signaling cascade that can act as a chemoattractant, or a general promoter of cell movement, proliferation, or differentiation in neural tissues.

Objectives: HGF/SF and Met are known to be expressed in the developing telencephalon and alterations in HGF/SF or Met expression appear to modulate proliferation and migration patterns of neurons. This study employed multiple lines of mutant mice to understand how changes in HGF/SF-Met signaling lead to alterations in neural circuitry and behavior. 

Methods: These studies employed transgenic mutant mouse lines with immunohistochemical, biochemical and anatomical studies to explore mechanisms of neural development.  In addition, behavioral testing in adult animals investigated whether developmental perturbations led to long term anxiety and learning and memory dysfunction.

Results: GABAergic interneuron numbers in the adult forebrain are regulated by embryonic levels of HGF/SF-Met signaling. Furthermore, the loss of Met signaling results in aberrantly splayed thalamocortical axon tracts and tortuous pyramidal neuron dendrites possibly leading to mistargeting of signals in the cerebral cortex and abnormal neural circuit formation. Targeted mutations lead to specific behavioral problems including seizures and procedural learning.

Conclusions: Our data suggest that Hgf and Met are required in the embryonic mouse forebrain for the proper development of various systems that are integral to proper neural circuitry formation.  Such disruptions can lead to profound neurological and behavioral consequences such as those portrayed in autism spectrum disorders.