Publication Date


Document Type

Doctoral Dissertation

Academic Program

Interdisciplinary Graduate Program


RNA Therapeutics Institute

First Thesis Advisor

Craig C. Mello


Cell Polarity, Caenorhabditis elegans Proteins, Cytoskeletal Proteins, Body Patterning, Cell Differentiation, Digestive System


Asymmetric cell divisions constitute a basic foundation of animal development, providing a mechanism for placing specific cell types at defined positions in a developing organism. In a 4-cell stage embryo in Caenorhabditis elegansthe EMS cell divides asymmetrically to specify intestinal cells, which requires a polarizing signal from the neighboring P2 cell. Here we describe how the extracellular signal from P2 is transmitted from the membrane to the nucleus during asymmetric EMS cell division, and present the identification of additional components in the pathways that accomplish this signaling.

P2/EMS signaling involves multiple inputs, which impinge on the Wnt, MAPK-like, and Src pathways. Transcriptional outputs downstream of these pathways depend on a homolog of β-catenin, WRM-1. Here we analyze the regulation of WRM-1, and show that the MAPK-like pathway maintains WRM-1 at the membrane, while its release and nuclear translocation depend on Wnt/Src signaling and sequential phosphorylation events by the major cell-cycle regulator CDK-1 and by the membrane-bound GSK-3 during EMS cell division. Our results provide novel mechanistic insights into how the signaling events at the cortex are coupled to the asymmetric EMS cell division through WRM-1.

To identify additional regulators in the pathways governing gut specification, we performed suppressor genetic screens using temperature-sensitive alleles of the gutless mutant mom-2/Wnt, and extra-gut mutant cks-1. Five intragenic suppressors and three semi-dominant suppressors were isolated in mom-2 suppressor screens. One extragenic suppressor was mapped to the locus ifg-1, eukaryotic translation initiation factor eIF4G. From the suppressor screen using cks-1(ne549), an allele of the self-cleaving nucleopore protein npp-10 was identified as a suppressor of cks-1(ne549)and other extra-gut mutants.

Taken together, these results help us better understand how the fate of intestinal cells are specified and regulated in early C. elegans embryos and broaden our knowledge of cell polarity and fate specification.



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