Programmed cell death or apoptosis is a fundamental, highly conserved pathway in animal development, and plays critical roles in normal health, as well as in aging and disease. Apoptotic cells must shut themselves down while leaving surrounding cells and tissues intact, and part of this process involves changes in the cytoskeleton of the apoptotic cells. Studies in the genetic model system C. elegans identified many of the key molecules that regulate and execute apoptosis, and this grant uses C. elegans as a system to understand the apoptotic regulation of the microtubule cytoskeleton. The study focuses on adult gonads, where about 50% of germ cells normally undergo apoptosis. The gonad is an example of a syncytial tissue, where individual "cells" maintain small cytoplasmic connections with neighboring cells. In a syncytium, the apoptotic removal of nuclei and cytoplasm must be tightly controlled to prevent death of the whole. The connections between "cells" present the possibility that part or all of the apoptotic cytoplasm might be transferred intact to the syncytium, rather than simply being degraded and recycled as metabolites. This grant examines how the normal microtubule cytoskeleton is dismantled during germ cell apoptosis, and how the new cytoskeleton is organized. It addresses the fate of cytoplasmc components of the apoptotic cell, and whether the new MT cytoskeleton contributes to the transfer of cytoplasm. Through either transfer or digestion, the apoptotic cell ultimately shrinks its cytoplasm, dismantles its cytoskeleton entirely, and is absorbed by other cells. This study identifies a role for the conserved kinase PAR-1 in the final steps of apoptotic remodeling, and addresses possible steps that might be regulated by PAR-1 activity.

Public Health Relevance

Apoptosis is a fundamental pathway of normal development and immune regulation, and involved in a vast array of human diseases including cancer, neurodegeneration and autoimmune disease. Studies using the model system C. elegans have had a major impact on the molecular understanding of apoptosis. Here, we use this system to address how the cytoskeleton is modulated and functions during the programmed death of C. elegans germ cells.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM107474-02
Application #
8720793
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98109