Randy Hewes

Randall S. Hewes, Ph.D.
Associate Professor of Zoology, Adjunct Associate Professor of Cell Biology

Welcome to the Hewes lab!!

Insect neuroendocrine cell axon with large dense core granules Larval Drosophila CNS labeled for dimm (green) and RFamide-related peptides (red)
hewes<<at>>ou.edu    405.325.6099

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Overview and Questions                                                                          

Our research aim is to understand the mechanisms underlying the long-term regulation of neuropeptide signaling.  In this research, we are using the powerful molecular and genetic techniques available in a model genetic organism, the fruit fly, Drosophila melanogaster.

Acting as neuromodulators and hormones, neuropeptides are key regulators of diverse processes, including growth, reproduction, stress, energy balance, sleep, and circadian rhythms. While there are exceptions, peptidergic cells as a rule, and neurosecretory cells in particular, synthesize prodigious amounts of neuropeptides. This is often to support chronic secretion or to overcome dilution of neuropeptides upon their release into the general circulation. One of the most fundamental characteristics of many neuropeptide systems is their inherent flexibility, which enables organisms to dramatically alter neuropeptide expression in response to internal and external cues. The resulting changes in the gain of neuropeptide signaling form an integral component of the neuroendocrine and physiological feedback loops that establish and regulate many homeostatic mechanisms. This form of regulation has been intensively investigated in a few amenable systems, and contributions of factors such as CREB and steroids to changes in neuropeptide gene expression are well documented. Nevertheless, in many other systems, the heterogeneity and scattered distribution of peptidergic cells has restricted progress toward a general molecular understanding of the mechanisms governing changes in neuropeptide expression and secretion, and new tools and approaches are needed.

There are three critical and largely unanswered questions that must be addressed for a full understanding of how neuropeptide systems are regulated. First, how is the development of neuropeptide-secreting (peptidergic) cells controlled? Second, what are the mechanisms underlying long-term changes in neuropeptide expression? Third, to what extent are genes that are involved in the development of peptidergic cells reused to perform similar functions in mature cells. We seek to address these questions in model systems where novel features of molecular signaling pathways can be isolated and readily studied, and where we can take full advantage of remarkable new tools that allow us to either raise or lower gene expression in specific neuropeptide-secreting cells, and also to dictate the precise timing of these changes.

Current Research Projects

dimm controls neuropeptide levels. Anti-leucokinin neuropeptide immunostaining in brain (insets) and ventral CNS of heterozygous control (+/-) and homozygous dimm mutant (-/-) larvae.
1. Peptidergic cell regulation by dimm.
In many professional secretory cells, the majority of new protein synthesis is devoted to the manufacture and storage of secreted proteins. Thus, there appear to be genetic factors that control robust expression of neuropeptides and other components of the regulated secretory pathway. We have identified a Drosophila basic helix-loop-helix (bHLH) gene, dimmed (dimm), with an expression pattern that corresponds precisely with neuronal and endocrine cells that accumulate large amounts of secretory peptides. Through genetic and cell biological methods, we have shown that dimm controls levels of a wide variety of neuropeptides and peptide biosynthetic enzymes within these diverse cells and that its actions appear to be confined to that aspect of cellular differentiation. Therefore, dimm appears to be an integral component of a novel and general mechanism by which secretory cells acquire and maintain the pro-secretory state. In our studies of dimm, and of the putative mouse ortholog, Mist1, we are using a variety of genetic, molecular and cell biological tools to further understand how neuropeptide levels are regulated in developing and mature animals.

2. Neuropeptide signaling pathways controlling insect wing expansion behavior.
Through their life-cycles, insects must go through repeated molts in order to accommodate increases in body size and changes in external morphology. At the end of each molt, insects perform highly stereotyped patterns of behavior in order to shed the old external cuticle. These events are triggered and controlled by neuropeptides. During the molt to the adult stage, many insects also perform additional neuropeptide-mediated behaviors to expand their wings. These are fascinating biological processes, and many of us have vivid childhood memories of watching a butterfly emerging from its chrysalis. However, they also present a unique opportunity for genetic analysis of neuropeptide signaling pathways controlling animal behavior. We are using genetic tools to define the relationships among cells controlling these behaviors and to identify novel mechanisms controlling neuropeptide signaling in this system.

Research Openings in the Lab

There are exciting opportunities available in my lab for postdoctoral, graduate, and undergraduate research on dimm, wing expansion, and related questions.  These include:

  1. Genetic and molecular screens for additional factors that function with dimm in controlling secretion in neuroendocrine and endocrine cells.
  2. Cell biological studies to further dissect the role of dimm and other proteins in controlling the regulated secretion of neuropeptides.
  3. Genetic, cell biological and molecular studies of the mouse dimm orthologue and its roles in controlling neuropeptide levels in embryos and adults.
  4. Molecular genetics and genomics approaches to study the roles of neuropeptides (and the cells that secrete them) in controlling behavior, physiology and development.

For more information on opportunities for undergraduate and graduate research in my lab, please feel free to call me, send me an e-mail (hewes<<at>>ou.edu), or drop in for a visit.


Recent Publications

  • Zhao, T., Gu, T., McAdams, K.L., Moran, E.P., and Hewes, R.S. (2010). The Split ends (SPEN) transcriptional coregulator suppresses Myosin II-dependent axon outgrowth during neurosecretory cell remodeling in Drosophila. Accepted pending minor revisions.
     
  • Hewes, R.S. (2008). The buzz on fly neuronal remodeling. TRENDS in Endocrinology and Metabolism 19:317-323 (pdfs).
     
  • Zhao, T., Gu, T., Rice, H.C., McAdams, K.L., Roark, K.M., Lawson, K., Gauthier, S.A., Reagan, K.L., and Hewes, R.S. (2008). A Drosophila gain-of-function screen for candidate genes controlling steroid-dependent neuroendocrine cell remodeling. Genetics 178:883-901. (pdfs)
     
  • Shakiryanova, D., Klose, M., Zhou, Y., Gu, T., Deitcher, D.L., Atwood, H.L., Hewes, R.S. and Levitan, E.S. (2007). Presynaptic ryanodine receptor-activated calmodulin kinase II increases vesicle mobility and potentiates neuropeptide release. Journal of Neuroscience 27(29):7799-7806. (pdfs)
     
  • Hewes, R.S., Gu, T., Brewster, J.A., Qu, C. & Zhao, T. (2006). Regulation of secretory protein expression in mature cells by DIMM, a bHLH neuroendocrine differentiation factor. Journal of Neuroscience 26(30):7860-7869. (pdfs)
  • Gauthier, S.A., and Hewes, R.S. (2006). Transcriptional regulation of neuropeptide and peptide hormone expression by the Drosophila dimmed and cryptocephal genes. Journal of Experimental Biology 209(10):1803-1815 (and cover photo). This article was also featured in the column, Inside JEB [K Phillips (2006). DIMM Regulates Neuropeptide Levels. J. Exp. Biol. 209(10):i-a]. (pdfs)
  • Sturman, D.A., Shakiryanova, D., Hewes, R.S., Deitcher, D.L. & Levitan, E.S. (2006). Nearly neutral secretory vesicles in Drosophila nerve terminals. Biophysical Journal 90(6):L45-L47. (pdfs)
     
  • Shakiryanova, D., Tully, A., Hewes, R.S., Deitcher, D.L. & Levitan, E.S. (2005). Activity-dependent liberation of synaptic neuropeptide vesicles. Nature Neuroscience 8:173-178. (pdfs)

Image Captions:

Upper left  Transmission electron micrograph of an insect neuroendocrine cell axon packed with numerous large dense core granules containing the neuropeptide, bursicon (image by P. Taghert, circa 1980; reprinted with permission).

Upper right  Confocal micrograph of a portion of the larval central nervous system showing the expression pattern of dimmed (green) and multiple neuropeptides ending in the C-terminal sequence, RF-amide (red).  Double-stained cells are yellow.



Page author: R.S. Hewes
Last modified: 7/15/10