The assembly of neurons into functional neural networks underlies all aspects of behavior-from simple sensory reflexes and motor responses to more complex cognitive functions. Within the developing vertebrate central nervous system, perhaps the simplest neural circuit is that coordinating sensory input with motor output-the monosynaptic stretch reflex circuit of the spinal cord. The function of this circuit depends on the selective interconnections of three major classes of neurons: motor neurons, primary sensory neurons, and a set of ventral interneurons that regulates the output of motor neurons. Understanding how this simple circuit is generated during development depends first on defining how the distinct identities of these specific neuronal subtypes if acquired. For it is the early acquisition of such subtype identities that provides neurons with the ability to form selective connections with specific neural targets. The major aim of this project is therefore to define the molecular mechanism that controls the differentiation of motor neurons and interneurons that underlie the formation and function of motor circuits in the developing spinal cord. The project will focus in particular on the key role of transcription factors in the specification of neuronal subtype identity in the ventral spinal cord. Our previous studies have begun to provide evidence that genes encoding two classes of homeodomain proteins, the Pax and Nhr genes have critical roles in defining motor neuron and ventral interneuron identity and eventually their connectivity. The present proposal will attempt to define in molecular detail the function of these transcription factors in directing the identity and assembly of neuronal subtypes in the developing mammalian spinal cord. These studies should therefore provide a first step towards the understanding of the molecular basis of neuronal circuit formation and its control of a simple motor behavior. We propose to define the mechanisms whereby distinct classes of motor neurons and interneurons are generated. To this end, we propose to carry out three specific sets of experiments. 1. Defining Pax6 Functions in Shh Signaling and Ventral Patterning. 2. Defining the Role of Nkx Genes in Shh Signaling and Ventral Patterning. 3. Analysis of Ventral Patterning Defects in Compound Nkx2.2 and Nkx2.9, Pax6, NKx2.2, and Pax6 x Nkx2.9 Mutants.
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