Function &Structure Adaptation in Forebrain Development

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): The migration of cells from their birthplace in embryonic proliferative zones of the forebrain to their final resting position is a key event in brain development. Cell migration requires initiation of movement, guidance through a complex terrain, and cessation at the appropriate time and place to integrate into developing circuits. Cell migration defects in the forebrain may contribute to mental retardation, epilepsy and neuropsychiatric disorders. Converging anatomical and genetic evidence supports the origin of neocortical GABAergic interneurons in the basal forebrain. These neurons arise from the ventrally located ganglionic eminence (GE) and migrate trans-telencephalically into the neocortex and hippocampus. From a developmental perspective, it is particularly important to define the molecular cues that regulate interneuron migration out of the GE into the neocortex, as disruption of this process could lead to significant changes in either the number or distribution of GABAergic neurons throughout the forebrain. In the context of altered function, there has been a longstanding interest in understanding impaired GABAergic transmission as an underlying component of mood disorders, for example anxiety and depression. We initiated studies of a complex signaling system that includes hepatocyte growth factor/scatter factor (HGF), a pleiotrophic molecule which, by signaling through its receptor, MET, induces motogenic, mitogenic, chemoattractive and differentiation activities in both neural and non-neural tissues. Our initial studies showed that HGF is a key molecular constituent in guiding interneuron migration out of the GE to the neocortex. Because genetic deletion of either Hgf or MET results in midgestional lethality, we have analyzed mice with a mutation of the gene encoding the urokinase-type plasminogen activator receptor (u-PAR), a component of the HGF-MET signaling system that activates HGF. In these mice, which survive into adulthood, interneuron migration is disrupted severely, providing evidence for HGF mediation of this process. Adult u-PAR-/- mice exhibit a substantial depletion of cortical interneurons and disruption of circuit function, expressed in the form of an altered anxiety state and spontaneous, intermittent seizures. These findings raise a number of important issues, which we propose to address in three specific aims. Morphological, molecular and behavioral analyses of the u-PAR-/- mice will be performed to define the adaptations in GABA function and interneuron development that may account for abnormal anxiety levels and altered excitability. We will examine the role of u-PAR signaling in mediating HGF-dependent interneuron development, using molecular and biochemical approaches to investigate the dynamic interactions between the HGF/MET and u-PA/u-PAR signaling systems. Finally, we will dissect genetically the HGF and MET signaling pathways in the forebrain by creating and analyzing new mouse lines in which regionally-selected deletions of each gene are accomplished by crossing existing lines carrying floxed alleles with forebrain promoter-driven Cre mice. The characterization of these mouse lines will provide novel models for investigations of adaptations in cortical circuits induced by developmental defects in interneuron migration.