Date of Award

Spring 1-1-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Min Han

Second Advisor

Thomas Blumenthal

Third Advisor

Michael Klymkowsky

Fourth Advisor

Jingshi Shen

Fifth Advisor

Angeles Ribera

Abstract

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.

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