Date of Award
Doctor of Philosophy (PhD)
The heterochronic gene network controls developmental timing in the nematode roundworm Caenorhabditis elegans. Bi-stable switch-like changes in gene expression occur during its development as stage-specific microRNAs are expressed and subsequently down-regulate other stage-specific factors, allowing for developmental progression. Key genes in this regulatory network are phylogenetically conserved and include the post-transcriptional microRNA repressor lin-28; the nuclear hormone receptor daf-12; and the microRNAs lin-4, mir-48, mir-84, mir-241, and let-7. daf-12 is the only factor currently known to regulate transcription of the Let-7 microRNA family, but its contribution is insufficient to account for all of the transcriptional regulation observed. In this work, a forward genetic screen is successfully used to identify a pathway that is genetically redundant with daf-12 in the regulation of developmental timing. This pathway is determined to require post-embryonic activity of the GATA-family transcription factor elt-1 and shown to likely act by directly regulating transcription of the Let-7 microRNA family during late larval developmental stages.
In a separate effort, the activated let-60/Ras Suppressor sur-4 is positionally cloned and shown to encode an allele of cnk-1, the C.elegans ortholog of the Drosophila gene connector enhancer of ksr. The suppressor allele of cnk-1 has a mutation in a conserved residue in its PH-domain and is predicted to have defects in plasma membrane localization.
Cohen, Max Louis, "Regulation of C. elegans Developmental Timing by the GATA Transcription Factor elt-1" (2013). Molecular, Cellular, and Developmental Biology Graduate Theses & Dissertations. 18.