Intellectual merit: This proposal aims to understand fundamental molecular mechanisms involved in developmental timing, the process that coordinates the synchrony and synchronization of tissue and organ formation. The experimental model is the nematode Caenorhabditis elegans where a number of genes are known to control the succession of events during the animal's larval stages. One of these genes, lin-28, is especially of interest because its homologs in mammals and other animals display precisely timed developmental expression, suggesting it is a conserved timing regulator in diverse animal species. Mutants defective in lin-28 skip developmental events specific to the second larval stage in many tissues, and later events occur precociously. Evidence now suggests that lin-28 opposes the activity of microRNAs (a newly-discovered class of small RNA regulators) and another heterochronic gene, lin-46, in the regulation of hbl-1. hbl-1 is a homologue of fly developmental transcription factor Hunchback and has an important role in controlling cell fates. lin-28 encodes a protein that acts on mRNA. The hypothesis to be tested is that the LIN-28 protein binds the hbl-1 mRNA and inhibits its repression by blocking the action of the miRNAs. The experiments will test whether lin-28 controls hbl-1 expression through its 3' UTR to control developmental timing. Broader impacts: The research will be performed by high school students, undergraduates, and doctoral candidates. The project will be conducted at an institution without an undergraduate population, therefore undergraduate students will be recruited from around the Philadelphia/Camden region to participate the research. High school students will spend afternoons working on independent aspects of the project in preparation for science fairs. The PI is committed to reaching underserved and underprivileged individuals for these opportunities. Doctoral candidates will present their findings at international scientific conferences. All strains and reagents generated will be shared freely with other investigators.
