The brain's proper functioning depends on the establishment of diverse cellular phenotypes. Our research program addresses the mechanisms that regulate differentiation of neuroendocrine cells during development. We use Drosophila molecular genetics to examine the biology of a basic HLH protein called Dimmed. Our genetic studies indicate DIMM promotes neuroendocrine differentiation in two ways. First it supports specific cell fate decisions (e.g., specific peptide hormone expression) in collaboration with other factors. Additionally, DIMM individually and strongly regulates at least one common neuroendocrine gene (encoding a peptide biosynthetic enzyme called PHM): DIMM expression is normally coincident with PHM, and when DIMM is mis-expressed it confers a PHM phenotype onto most or all brain cells. DIMM is related to the mammalian protein Mist1, a factor also implicated in neuroendocrine differentiation. We hypothesize that DIMM is a dedicated, pro-secretory regulatory factor with conserved functions, whose study will lead to a better understanding of the organization and differentiation of neuroendocrine cell types. This basic research program will support efforts to address human syndromes caused by underlying neuroendocrine disorders, such as stress, or tumor formation in the pituitary or pancreas, and will help guide future programs of stem cell differentiation to generate specific neuroendocrine lineages in vitro. To pursue this research program, we propose three specific aims. First we will examine the mechanisms by which DIMM collaborates with other factors to promote specific peptide hormone expression by subsets of neuroendocrine cells. Second we will examine mechanisms by which DIMM promotes a common program of differentiation for all neuroendocrine cells. We hypothesize that program represents expression of a core set of genes, one of which we have identified as PHM. Because dimm expression predicts and defines subsequent neuroendocrine differentiation, the factors working upstream of dimm are significant. Therefore, the third aim plans genetic screens to identify factors that regulate dimm expression.
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