DIMM REGULATES NEUROPEPTIDE LEVELS

Abstract

There are few molecules in biology as powerful as neuropeptides. Regulating a host of physiological functions from growth and reproduction to sleep and circadian rhythms, neuropeptides are essential for many aspects of life. Randall Hewes from the University of Oklahoma explains that neuropeptide expression levels vary hugely in response to physiological stimuli, and that the expression of these neural signalling molecules is tightly regulated. One of the few proteins that is known to regulate neuropeptide levels in Drosophila is the DIMM transcription factor, which is expressed widely in neural tissue. But which neuropeptides are regulated by DIMM and how the transcription factor functions wasn't clear. Hewes and Sebastian Gauthier began comparing mutant Drosophila that lacked a functional dimm gene with natural flies to see which neuropeptides were regulated by the transcription factor(p. 1803).The team decided to compare the cellular levels of mRNA for 16 neuropeptide and associated protein genes in mutant fly larvae, which lacked a functional dimm gene, with the mRNA levels of the same neuropeptides in natural fly larvae, which retained the intact transcription factor gene. But the team faced a complication. Hewes explains that all of the dimm mutant flies also carried a mutation in another transcription factor gene, cryptocephal, due to difficulties controlling the exact location of the mutation in Drosophila. So the team had to make sure that they also monitored the 16 genes' mRNA levels in fly larvae where cryptocephal alone was mutated to make sure that any differences between the mutant and natural flies were due to the dimm gene.Quantifying the mRNA level differences between the natural and mutated fly larvae, Gauthier and Hewes clearly saw that the mRNA from three neuropeptide genes fell dramatically in the mutant animals: Dromyosuppressin,FMFRamide-related and Leucokinin were all transcriptionally regulated by DIMM. The team suspects that DIMM also regulates the protein levels of other neuropeptide genes through other cellular mechanisms.However, the team was in for a shock when they looked at the mRNA levels in their control flies. All but one of the monitored genes behaved exactly like the genes in the natural fly larvae, but when they measured the level of Ecdysis triggering hormone (ETH) in the cryptocephal mutant flies,the hormone's level was severely reduced. Cryptocephal controls ETH levels. They had inadvertently discovered one of the genes that cryptocephal targets.Hewes explains that the cryptocephal mutation was first identified in 1942, when flies lacking the gene were found to fail to complete ecdysis. Now that Hewes and Gauthier have found this critical link between cryptocephal and the hormone that orchestrates ecdysis, they would like to know exactly how cryptocephal regulates ETH levels.