Normal brain 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 (DIMM). Our genetic studies indicate DIMM is necessary and sufficient to promote the cellular features that define neuroendocrine differentiation. First, DIMM is normally expressed by most of the principal peptidergic cells in Drosophila (though not all). Loss-of-function analysis indicates DIMM is not required for cell survival or growth, but is required for these cells to display a proper regulated secretory pathway and normal accumulation of neuropeptides. Gain-of-function studies indicate DIMM can activate the cellular machinery to support peptidergic function in non-peptidergic (i.e., conventional) neurons. At a molecular level, we have shown that DIMM is a transcription factor and that it activates several specific target genes. DIMM is related to the mammalian protein Mist1, a factor implicated in secretory cell differentiation. We hypothesize that DIMM is a dedicated, pro-secretory factor with conserved functions, whose study will lead to a better understanding of the organization and differentiation of neuroendocrine cell types. This research program supports 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. Here we propose five specific aims. First we will derive a consensus DIMM cis-binding site by analyzing in vitro and in vivo several direct target genes. Second, we will extend the list of molecular targets. Third, we will examine DIMM action mechanisms by genetically testing the roles of individual DIMM targets. Fourth, we will test the hypothesis that the paired homeoprotein Eyeless is the principal activator of dimmed. Finally, we will extend our analysis to the mouse model system by examining the hypothesis that the DIMM orthologue Mist1 plays an important role in mammalian peptidergic cell biology.

Public Health Relevance

We study the developmental mechanisms used by neurons to acquire their mature properties. This is significant because the proper functioning of the brain relies on the precision with which different categories of neurons are correctly assembled. In particular, we focus on peptidergic neurons that produce critical signals to coordinate normal physiology and behavior. Our work could help address diverse physiological, emotional and cognitive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021749-26
Application #
8209172
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Mamounas, Laura
Project Start
1985-07-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
26
Fiscal Year
2012
Total Cost
$387,324
Indirect Cost
$132,506
Name
Washington University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Diao, Feici; Mena, Wilson; Shi, Jonathan et al. (2016) The Splice Isoforms of the Drosophila Ecdysis Triggering Hormone Receptor Have Developmentally Distinct Roles. Genetics 202:175-89
Hadžić, Tarik; Park, Dongkook; Abruzzi, Katharine C et al. (2015) Genome-wide features of neuroendocrine regulation in Drosophila by the basic helix-loop-helix transcription factor DIMMED. Nucleic Acids Res 43:2199-215
Beebe, Katherine; Park, Dongkook; Taghert, Paul H et al. (2015) The Drosophila Prosecretory Transcription Factor dimmed Is Dynamically Regulated in Adult Enteroendocrine Cells and Protects Against Gram-Negative Infection. G3 (Bethesda) 5:1517-24
Park, Dongkook; Li, Peiyao; Dani, Adish et al. (2014) Peptidergic cell-specific synaptotagmins in Drosophila: localization to dense-core granules and regulation by the bHLH protein DIMMED. J Neurosci 34:13195-207
Taghert, Paul H; Nitabach, Michael N (2012) Peptide neuromodulation in invertebrate model systems. Neuron 76:82-97
Park, Dongkook; Hou, Xiaowen; Sweedler, Jonathan V et al. (2012) Therapeutic peptide production in Drosophila. Peptides 36:251-6
Mills, Jason C; Taghert, Paul H (2012) Scaling factors: transcription factors regulating subcellular domains. Bioessays 34:10-6
Park, Dongkook; Hadžić, Tarik; Yin, Ping et al. (2011) Molecular organization of Drosophila neuroendocrine cells by Dimmed. Curr Biol 21:1515-24
Hamanaka, Yoshitaka; Park, Dongkook; Yin, Ping et al. (2010) Transcriptional orchestration of the regulated secretory pathway in neurons by the bHLH protein DIMM. Curr Biol 20:9-18
Park, Dongkook; Taghert, Paul H (2009) Peptidergic neurosecretory cells in insects: organization and control by the bHLH protein DIMMED. Gen Comp Endocrinol 162:2-7

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