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The Journal of Neuroscience, July 26, 2006, 26(30):7860-7869; doi:10.1523/JNEUROSCI.1759-06.2006
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Development/Plasticity/Repair
Regulation of Secretory Protein Expression in Mature Cells by DIMM, a Basic Helix–Loop–Helix Neuroendocrine Differentiation Factor
Randall S. Hewes,1,2 Tingting Gu,1 Jordan A. Brewster,1 Chunjing Qu,1 andTao Zhao1 1Department of Zoology, University of Oklahoma, Norman, Oklahoma 73019, and 2Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104
Correspondence should be addressed to Randall Hewes, Department of Zoology, Stephenson Research and Technology Center, 101 David L. Boren Boulevard, University of Oklahoma, Norman, OK 73019. hewes{at}ou.edu
During differentiation, neuroendocrine cells acquire highly amplified capacities to synthesize neuropeptides to overcome dilution of these signals in the general circulation. Once mature, the normal functioning of integrated physiological systems requires that neuroendocrine cells remain plastic to dramatically alter neuropeptide expression for long periods in response to hormonal and electrical cues. The mechanisms underlying the long-term regulation of neuroendocrine systems are poorly understood. Here we show that the Drosophila basic helix-loop-helix protein DIMM, a critical regulator of neuroendocrine cell differentiation, controls secretory capacity in mature neurons. DIMM expression began embryonically but persisted in adults. Through spatial and temporal manipulation of transgene expression in vivo, we defined two phases of prosecretory DIMM activity. During an embryonic critical window, DIMM controlled the differentiation of amplified expression of the neuropeptide leucokinin. At the onset of metamorphosis, levels of DIMM decreased in the insulin-producing cells (IPCs) in parallel with a marked reduction in levels of Drosophila insulin-like peptide 2 and a key neuropeptide biosynthetic enzyme peptidylglycine
-monooxygenase (PHM). Overexpression of DIMM in the IPCs prevented the decrease in PHM levels at this stage. In addition, transient overexpression of DIMM in adults produced a dramatic increase in PHM levels in numerous neurons located throughout the brain. These findings provide insights into the mechanisms controlling the maintenance of differentiated cell states, and they suggest an effective means for dynamically adjusting the strength of hormonal signals in diverse homeostatic systems.
Key words: Drosophila; basic helix-loop-helix; Mist1; dimmed; Atonal; leucokinin; PHM
Received April 25, 2006; revised June 19, 2006; accepted June 21, 2006.
Correspondence should be addressed to Randall Hewes, Department of Zoology, Stephenson Research and Technology Center, 101 David L. Boren Boulevard, University of Oklahoma, Norman, OK 73019. hewes{at}ou.edu
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