The human brain consists of over one hundred billion neurons assembled into functional neural circuits, which underlie all sophisticated brain functions. A precise balance between neuronal excitation and inhibition is required for proper brain function, and the imbalance between them leads to various types of behavioral and neurological problems including many complex brain disorders, such as schizophrenia, depression, and autism. Regulatory mechanisms for excitatory and inhibitory neuron formation have been studied in great detail, but those mechanisms regulating inhibitory interneurons are still being elucidated. The overarching goal of this project is to better understand the regulatory pathways underlying inhibitory interneuron formation with the hope that such insight will lead to the better understanding of complex brain disorders and the development of effective therapeutics. In order to reach this goal, we began by identifying factors that could potentially affect the development of the embryonic ganglionic eminences (GE), a ventral forebrain region where inhibitory interneurons are born. We rationalized that such factors should be expressed in the GE and regulate signaling pathways essential for controlling neurogenesis. Our initial studies reveal that Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, satisfies these criteria. We have found that Nlk (mouse homologue of NLK) is specifically expressed in different regions of the GE, and loss of Nlk in mice causes a dramatic increase in the proliferation of neural progenitor cells and impairment of their differentiation into mature inhibitory interneurons. Based on these preliminary studies, we hypothesize that Nlk plays a fundamental role in the development of inhibitory interneurons. To investigate this idea, we propose the following two major aims. In Aim 1, we will determine the role of Nlk in the control of neural progenitor cell proliferation in the mouse GE. We will investigate specifically when, and how, Nlk influences progenitor cell number in specific regions of the GE. In Aim 2, we will examine if Nlk is required for the proper differentiation and maintenance of specific subtypes of inhibitory interneurons in the cortex and striatum during embryonic and adult stages. We believe that the knowledge gained from the studies proposed in this application will fundamentally advance our understanding of the regulatory mechanisms of normal inhibitory interneuron formation, and thus provide insights into the relevance of this important process to understanding the pathogenesis of complex brain disorders.