|Assistant Professor, Biological Chemistry|
|Member, Cell & Developmental Biology GPB Home Area, Genetics & Genomics GPB Home Area, Molecular, Cellular & Integrative Physiology GPB Home Area|
The molting cycle typically involves extensive communication among neuroendocrine centers in the brain and peripheral tissues remodeled during molting. Although the endocrine control of molting is best understood in insects, neuroendocrine circuits that start, stop, and set the pace of the molting cycle are not well understood in any organism.
Every molt involves the coordinated, transient remodeling of tissues spread throughout the body. Epidermal cells fully remodel the local extracellular matrix (ECM) in addition to cell-ECM and cell-cell attachments. Particular epidermal cells also divide like stem cells near the time of the molt. Because the external skeleton of nematodes is a collagenous ECM similar to human skin and connective tissue, mechanisms for renewal of the worm skeleton will likely apply to ECM homeostasis in vertebrates, a process essential for normal development and wound repair. Faulty interactions among cells and the ECM promote the metastasis of tumors and also contribute to pathologies of skin and connective tissue in humans, including Marfan syndrome and certain muscular dystrophies.
Use of the model nematode C. elegans provides an exemplary opportunity to study the endocrine and enzymatic regulation of molting in an organism amenable to functional genomic, genetic, and cell biological analysis. In prior work, we identified scores of genes required for shedding the old skeleton through a genome-wide, reverse genetic screen using RNA-interference (RNAi). Fusions to GFP showed that eight of the genes are expressed in epidermal cells that synthesize the cuticle, in a pulse before ecdysis. These and other genes identified in our screen may contribute to remodeling of the exoskeleton.
Through our ongoing analysis of the C. elegans molting cycle, we expect to discover conserved signaling pathways and enzymatic cascades that promote remodeling of collagenous extracellular matrices. We further expect to find novel mechanisms for the neuroendocrine regulation of animal development and behavior. In addition, our research will identify potential targets for new drugs for diseases caused by parasitic nematodes currently affecting over 140 million people living primarily in tropical regions.
Alison joined the faculty of the Department of Biological Chemistry in the David Geffen School of Medicine at UCLA in March of 2007. She began studying the molting cycle of C. elegans as a post-doctoral research associate in the laboratory of Gary Ruvkun at Harvard Medical School. Her graduate research in Chris Kaiser's lab at the Massachusetts Institute of Technology defined an essential pathway for protein disulfide bond formation in the endoplasmic reticulum of yeast. Alison earned her bachelor degree from Cornell University, where she worked in the laboratory of Tom Fox.
Gomez Fernando, Monsalve Gabriela C, Tse Vincent, Saiki Ryoichi, Weng Emily, Lee Laura, Srinivasan Chandra, Frand Alison R, Clarke Catherine F Delayed accumulation of intestinal coliform bacteria enhances life span and stress resistance in Caenorhabditis elegans fed respiratory deficient E. coli. BMC microbiology. 2012; 12: 300.
Moissiard Guillaume, Cokus Shawn J, Cary Joshua, Feng Suhua, Billi Allison C, Stroud Hume, Husmann Dylan, Zhan Ye, Lajoie Bryan R, McCord Rachel Patton, Hale Christopher J, Feng Wei, Michaels Scott D, Frand Alison R, Pellegrini Matteo, Dekker Job, Kim John K, Jacobsen Steven E MORC family ATPases required for heterochromatin condensation and gene silencing. Science (New York, N.Y.). 2012; 336(6087): 1448-51.
Monsalve Gabriela C, Van Buskirk Cheryl, Frand Alison R LIN-42/PERIOD controls cyclical and developmental progression of C. elegans molts. Current biology : CB. 2011; 21(24): 2033-45.
Russel Sascha, Frand Alison R, Ruvkun Gary Regulation of the C. elegans molt by pqn-47. Developmental biology. 2011; 360(2): 297-309.
Meli Vijaykumar S, Osuna Beatriz, Ruvkun Gary, Frand Alison R MLT-10 defines a family of DUF644 and proline-rich repeat proteins involved in the molting cycle of Caenorhabditis elegans. Molecular biology of the cell. 2010; 21(10): 1648-61.
Frand Alison Alison Frand: Breaking out new ideas on molting. Interview by Caitlin Sedwick. The Journal of cell biology. 2008; 181(6): 876-7.
Hayes, G. D. Frand, A. R. Ruvkun, G. The mir-84 and let-7 paralogous microRNA genes of Caenorhabditis elegans direct the cessation of molting via the conserved nuclear hormone receptors NHR-23 and NHR-25. Development. 2006; 133(23): 4631-41.
Frand, A. R. Russel, S. Ruvkun, G. Functional genomic analysis of C. elegans molting. PLoS Biol. 2005; 3(10): e312.
Frand, A. R. Cuozzo, J. W. Kaiser, C. A. Pathways for protein disulphide bond formation. Trends Cell Biol. 2000; 10(5): 203-10.
Frand, A. R. Kaiser, C. A. Two pairs of conserved cysteines are required for the oxidative activity of Ero1p in protein disulfide bond formation in the endoplasmic reticulum. Mol Biol Cell. 2000; 11(9): 2833-43.
Frand, A. R. Kaiser, C. A. Ero1p oxidizes protein disulfide isomerase in a pathway for disulfide bond formation in the endoplasmic reticulum. Mol Cell. 1999; 4(4): 469-77.
Frand, A. R. Kaiser, C. A. The ERO1 gene of yeast is required for oxidation of protein dithiols in the endoplasmic reticulum. Mol Cell. 1998; 1(2): 161-70.
Chin Randall M, Fu Xudong, Pai Melody Y, Vergnes Laurent, Hwang Heejun, Deng Gang, Diep Simon, Lomenick Brett, Meli Vijaykumar S, Monsalve Gabriela C, Hu Eileen, Whelan Stephen A, Wang Jennifer X, Jung Gwanghyun, Solis Gregory M, Fazlollahi Farbod, Kaweeteerawat Chitrada, Quach Austin, Nili Mahta, Krall Abby S, Godwin Hilary A, Chang Helena R, Faull Kym F, Guo Feng, Jiang Meisheng, Trauger Sunia A, Saghatelian Alan, Braas Daniel, Christofk Heather R, Clarke Catherine F, Teitell Michael A, Petrascheck Michael, Reue Karen, Jung Michael E, Frand Alison R, Huang Jing The metabolite Î±-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014; .
Monsalve Gabriela C, Frand Alison R Toward a unified model of developmental timing: A "molting" approach. Worm. 2012; 1(4): 221-30.