Molecular Mechanisms Controlling Formation of Basal Ganglia Circuitry

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): The basal ganglia comprise a collection of nuclei that are primarily involved in controlling purposeful movements and appropriate behavior. The striatum represents the major component of the basal ganglia which functions by processing cortical inputs and subsequently regulates activity in the output nuclei (the entopeduncular nucleus and substantia nigra) through two distinct pathways. The direct pathway monosynaptically connects the striatum to the output nuclei, while the indirect pathway influences the output nuclei via the globus pallidus and subthalamic nucleus. It is believed that balanced output between these two pathways is required for normal brain function. Indeed, dysfunction of this circuit is known to underlie the abnormal movements observed in the neurodegenerative disorders, Parkinson's and Huntington's disease. Moreover, malfunction of this circuit has also been implicated in the neurodevelopmental disorders Tourette's syndrome and obsessive compulsive disorder (OCD). Currently, little is known about the molecular mechanisms underlying the formation of the striatal output pathways. Our fate mapping data indicates that the LIM homeodomain transcription factor Islet1 is expressed predominantly in the progenitors of the direct striatal output pathway. This proposal will examine the requirement for Islet1 in the correct formation of the direct striatal output pathways. In Specific Aim 1, we will determine the role of this transcription factor in the striatal progenitors, themselves. Specific Aim 2 will determine the requirement for Islet1 in the correct formation of the reticular thalamus and zona incerta as well as their subsequent role in the correct formation of the striatal output pathways. Finally, our preliminary data implicate PlexinD1-Sema3E signaling downstream of Islet1 in the formation of the direct striatal output pathways. Thus, Specific Aim 3 will address the role of PlexinD1 and Sema3E in the formation of the striatal output pathways. Elucidation of the mechanisms underlying the formation of basal ganglia circuitry may lead to a better understanding of the neuronal alterations in certain basal ganglia disorders as well as provide opportunities to develop better treatments for these conditions.