Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Genetics and Genomics

Language

English (en)

Date of Award

1-1-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Tim Schedl

Abstract

During normal development as well as in diseased states such as cancer, extracellular "niches" often provide cues to proximal cells and activate intracellular pathways. Activation of such signaling pathways in turn instructs cellular proliferation and differentiation. In the C.elegans gonad, GLP-1/Notch signaling instructs germ line stem cells to self renew through mitotic cell division. As germ cells progressively move out of the niche, they differentiate by entering meiosis and eventually form gametes. Using this model system, I uncovered a cooperative role for the METT-10 putative methyltransferase and the dynein motor complex in regulating the balance between germ cell proliferation and differentiation. I demonstrate that Dynein Light Chain-1: DLC-1), and its partner, Dynein Heavy Chain-1, inhibit the proliferative cell fate, in part through regulation of METT-10 levels and nuclear accumulation. I further show that the methyltransferase domain of METT-10 is required for normal inhibition of germ cell proliferation, and that DLC-1 and METT-10 act antagonistically to activation of the GLP-1 Notch pathway, which plays conserved roles in stem cell fate specification. Moreover, I find that regulation of germ cell proliferative fate is only one of multiple joint functions of METT-10 and the dynein motor complex, and propose that they function together in multiple cellular contexts, including mitotic cell division. The finding that METT-10 and dynein inhibit germ cell proliferative fate, despite promoting mitotic cell division of those cells that do proliferate, highlights a genetic difference between the specification of proliferative fate and its execution.

Comments

Permanent URL: http://dx.doi.org/10.7936/K72J68WM

Download

Share

COinS