The C. elegans model system is ideal for studying the genetic and molecular mechanisms of the control of cell division and differentiation in vivo. We focus on the epidermal "seam cells" that undergo a stereotyped pattern of divisions throughout larval development, followed by terminal differentiation at adulthood. Seam cells exhibit stem-cell- like behavior, including self-renewal through either asymmetric or symmetric cell division. The execution of symmetric and asymmetric cell divisions by seam cells is regulated by developmental timing mechanisms that have been extensively characterized in our lab. In the first Aim of the project, we will explore how developmental timing regulators interface with pathways affecting cell division polarity to control when seam cells switch from asymmetric to symmetric cell division.
The second Aim will extend these studies to identify new genes that affect the regulation of symmetric vs. asymmetic cell divisions in seam cells.
The third Aim will utilize C. elegans as a model to study the mechanisms governing stem cell quiescence. Mammalian adult stem cells commonly transition between proliferative and quiescent states, depending on extracellular signals. During quiescence, a stem cell's vitality and developmental potential is maintained for extended periods of time. We propose to learn about mechanisms that controlling stem cell maintenance during quiescence in dauer larva developmental arrest. The dauer larva is an optional developmentally-arrested second stage larva that is induced in response to environmental conditions unfavorable for growth. In dauer larvae, the seam cells enter quiescence, and remarkably, this quiescence profoundly affects how seam cells respond to certain developmental regulatory genes, including the evolutionarily conserved lin-4 and let-7 microRNA genes. Studying how developmental quiescence interacts with developmental timing regulators in C. elegans cell lineages should reveal fundamental principles of stem cell behavior relevant to human biology, including development, cancer, tissue homeostasis and wound healing.

Public Health Relevance

C. elegans is an excellent system for the genetic analysis of developmental processes in animals, including the control of cell division, cell number, and cellular differentiation. Since many of the proteins and other regulatory molecules that control C. elegans development are also found in mammals, understanding their roles in C. elegans should reveal the mechanisms and principles underlying developmental processes common to all animals, including humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034028-27
Application #
8245767
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
1984-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
27
Fiscal Year
2012
Total Cost
$407,017
Indirect Cost
$159,590
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
McJunkin, Katherine; Ambros, Victor (2014) The embryonic mir-35 family of microRNAs promotes multiple aspects of fecundity in Caenorhabditis elegans. G3 (Bethesda) 4:1747-54
Nelson, Charles; Ambros, Victor; Baehrecke, Eric H (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell 56:376-88
Zinovyeva, Anna Y; Bouasker, Samir; Simard, Martin J et al. (2014) Mutations in conserved residues of the C. elegans microRNA Argonaute ALG-1 identify separable functions in ALG-1 miRISC loading and target repression. PLoS Genet 10:e1004286
Zou, Yan; Chiu, Hui; Zinovyeva, Anna et al. (2013) Developmental decline in neuronal regeneration by the progressive change of two intrinsic timers. Science 340:372-6
McManus, David D; Ambros, Victor (2011) Circulating MicroRNAs in cardiovascular disease. Circulation 124:1908-10
Ambros, Victor (2011) MicroRNAs and developmental timing. Curr Opin Genet Dev 21:511-7
Karp, Xantha; Ambros, Victor (2011) The developmental timing regulator HBL-1 modulates the dauer formation decision in Caenorhabditis elegans. Genetics 187:345-53
Hammell, Christopher M; Lubin, Isabella; Boag, Peter R et al. (2009) nhl-2 Modulates microRNA activity in Caenorhabditis elegans. Cell 136:926-38
Zhang, Liang; Hammell, Molly; Kudlow, Brian A et al. (2009) Systematic analysis of dynamic miRNA-target interactions during C. elegans development. Development 136:3043-55
Hong, Xin; Hammell, Molly; Ambros, Victor et al. (2009) Immunopurification of Ago1 miRNPs selects for a distinct class of microRNA targets. Proc Natl Acad Sci U S A 106:15085-90

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