Joint Functions of METT-10 and Dynein in the Caenorhabditis elegans Germ Line

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 <italic>C.elegans</italic> 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.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Biology and Biomedical Sciences: Molecular Genetics and Genomics

Year dc:date.available

2012

Author dc:creator

• Dorsett, Maia

Contributors dc:contributor

• Tim Schedl

• Biology
• Developmental biology
• Genetics
• C. elegans
• Dynein
• Germline
• METT-10
• Notch
• Stem cells

Language dc:language

English (en)

DOI

https://doi.org/10.7936/K72J68WM

OAI identifier oai:identifier

oai:openscholarship.wustl.edu:etd-1570