The mammalian brain is composed of a large and diverse number of neuronal phenotypes. These phenotypes are specified during CNS development by a complex interplay of cellular and molecular events. In humans, perturbations in this complex development of brain neurons may lead to deficits in CNS function associated with mental retardation or other neurologic disorders. At present we have only a minimal understanding of the cellular and molecular mechanisms thal regulate this specification of mammalian neuronal phenotypes. The identification of these mechanisms will be important in gaining a better understanding of CNS development. A neuron's phenotype is ultimately determined by the array of genes expressed within that particular cell and by the proteins that regulate transcription from these genes. The homeobox genes encode one class of proteins likely to play a role in determining a neuron's phenotype. These proteins appear to be transcriptional regulatory factors which are required for specification of cellular phenotypes. We are presently using recombinant DNA methodologies to identify homeobox genes expressed in mouse cerebellar granule neurons. A primary focus of our work is to study the expression of these homeobox genes in developing granule neurons. We are particularly interested in identifying molecular mechanisms responsible for regulating their expression. This regulation is likely to be critical for the specification of the granule neuron phenotype. Recent studies, evaluating CNS cell linages, have suggested that some CNS neuron phenotypes are determined by local interactions occurring after the last cell division. These interactions may occur as synaptic connections are made between developing neurons and their' targets. It is possible that these interaction involve neurotransmitters released from target neurons. We are presently evaluating whether neurotransmitters can modulate homeobox gene expression in developing cerebellar granule neurons in vitro. Preliminary data suggests that the level of transcripts encoding at least one homeobox gene is increased in response to the neurotransmitter glutamate. This modulation appears to be via activation of N-methyl-D-aspartate (NMDA) receptors. These studies will be extended to provide a more detailed characterization of the response of these cell to NMDA, including an evaluation of whether this modulation in RNA level is a result of changes in transcript synthesis.
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