Work in the Rougvie laboratory is directed at understanding how cells execute specific events at precise times during development. To understand how cellular timekeeping works, the lab has chosen to study a developmentally simply organism, the nematode Caenorhabditis elegans. The lab is dissecting the timing mechanism that restricts the differentiation of hypodermal cells to a time late in the life of the worm, the transition from the larval to adult form. The approach is to identify mutations that cause this event to occur at the wrong time during development, and then to study the genes defined by these mutations. These genes are referred to as ‘heterochronic’ genes because their mutation alters the relative timing and sequence of many developmental events in the animal.
One event timed by the heterochronic genes is the terminal differentiation of the lateral hypodermis, a process that is restricted to the final (fourth) molt in wild-type animals and called the larval-to-adult (L/A) switch. Mutations in heterochronic genes advance or retard the timing of the L/A switch, resulting in larvae with adult hypodermis or adults with larval hypodermis. We have identified several heterochronic genes through a variety of genetic screens. For example, mutation of the gene lin-42 causes the L/A switch to occur precociously, during the third molt. lin-42 encodes a protein that most closely resembles the PERIOD (PER) family of proteins from Drosophila and other organisms. This result is particularly intriguing because PER proteins regulate circadian rhythms, a second type of biological timing mechanism in animals: the internal clock that controls the approximately 24-hour oscillation of biological processes such as sleep-wake cycles. Experiments are underway to investigate the similarities between LIN-42 and PER and to understand how LIN-42 functions in the heterochronic gene pathway. Another heterochronic gene we identified is hbl-1, the orthologue of Drosophila hunchback. Studies of hbl-1 temporal regulation have led the lab to the study of microRNAs, tiny, ~22 nt non-coding RNAs that down-regulate gene expression by interacting with 3'UTRs of target genes.
The Rougvie lab will continue analysis of lin-42 and hbl-1 and its miRNA regulators, as well as additional genes identified through ongoing genetic screens in order to understand how the heterochronic gene pathway conveys temporal information to cells of the developing animal. The lab's long-term goal is to determine how developmental timing mechanisms are integrated with the spatial and sexual cues required for proper development of a multicellular organism.
Selected Publications (Pubmed Search)
Fukuyama, M., Rougvie, A. E., and Rothman, J. (2006) Nutrient-dependent arrest of cell cycle and growth in the C. elegans germline mediated by the DAF-18/PTEN tumor suppressor. Curr. Biol. 16, 773-779.
Tennessen, J. M., Gardner, H. F., and Rougvie, A. E. (2005). Novel heterochronic functions for the Caenorhabditis elegans period-related protein LIN-42. Dev. Biol. 289, 30-43.
Li, M., Jones-Rhoades, M. W., Lau, N. C., Bartel, D. P. and Rougvie, A. E. (2005) Regulatory mutations of mir-48, a C. elegans let-7 family microRNA, cause developmental timing defects. Dev. Cell 9, 415-422.
Rougvie, A. E. (2005). Intrinsic and extrinsic regulators of developmental timing: from miRNAs to nutritional cues. Development 132, 3787-3798.
Chan RC, chan A, Jeon M, Wu TF, Pasqualone D, Rougvie AE and Meyer BJ (2003) Chromosome cohesion is regulated by C. elegans TIM-1, a paralog of the clock protein TIMELESS. Nature, 424:1002-1009.
Abrahante, J. E., Daul, A. L., Li, M., Volk, M. L., Tennessen, J. M., Miller, E. A. and Rougvie, A. E. (2003) The Caenorhabditis elegans hunchback-like gene lin-57/hbl-1 controls developmental time and is regulated by microRNAs. Developmental Cell 4, 625-637.
Rougvie, A. E. (2001). Control of developmental timing in animals. Nature Rev. Gen. 2, 690-701.
Reinhart, B. J., Slack, F., Basson, M., Pasquinelli, A. E., Bettinger, J., Rougvie, A. E., Horvitz, H. R. and Ruvkun, G. B. (2000). The 21 nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403, 901-906.