It would be potentially advantageous if organs could be repopulated from a small number of cells that would remove and replace other cells during growth, preserving tissue dimensions during the replacement. Such a process can occur during development, where it is called """"""""cell competition"""""""". Cell competition is seen during insect development, mammalian embryogenesis, and liver regeneration, and implicated in tumor development. When tissues contain genetically distinct cell populations with different growth properties, the `stronger'genotype can completely eliminate the `weaker'genotype and come to fill the entire compartment. We have identified 16 genes that are required for cell competition, and found that it depends on recognition, engulfment and killing of susceptible cells by their normal neighbors. Our current goal is a cellular and molecular understanding of the pathways that recognize and eliminate cells, how such cells become targets for removal, and undergo apoptosis when so targeted, and the mechanisms by which out-competed cells are replaced to preserve tissue morphology. As cell competition occurs during mammalian liver regeneration, and is implicated in cancer, it is anticipated that anti-tumor therapies and strategies to assist regeneration of human organs can be based on these studies. Defective cell survival and cell corpse engulfment underlie neurodegenerative diseases, neuronal injuries, heart attack, stroke, atherosclerosis, angiogenesis, and infectious diseases including HIV/AIDS, autoimmune diseases, and blindness. It is anticipated that, should it prove possible to manipulate cell engulfment and killing downstream of growth differences between cells, strategies may be developed for the replacement of developmental compartments that do not require manipulating oncogenes or tumor suppressors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061230-08
Application #
7900352
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Hamlet, Michelle R
Project Start
2001-02-01
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
8
Fiscal Year
2010
Total Cost
$320,463
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Baker, Nicholas E; Kale, Abhijit (2016) Mutations in ribosomal proteins: Apoptosis, cell competition, and cancer. Mol Cell Oncol 3:e1029065
Fullard, John F; Baker, Nicholas E (2015) Signaling by the engulfment receptor draper: a screen in Drosophila melanogaster implicates cytoskeletal regulators, Jun N-terminal Kinase, and Yorkie. Genetics 199:117-34
Kale, A; Li, W; Lee, C-H et al. (2015) Apoptotic mechanisms during competition of ribosomal protein mutant cells: roles of the initiator caspases Dronc and Dream/Strica. Cell Death Differ 22:1300-12
Sidyelyeva, Galyna; Wegener, Christian; Schoenfeld, Brian P et al. (2010) Individual carboxypeptidase D domains have both redundant and unique functions in Drosophila development and behavior. Cell Mol Life Sci 67:2991-3004
Firth, Lucy C; Bhattacharya, Abhishek; Baker, Nicholas E (2010) Cell cycle arrest by a gradient of Dpp signaling during Drosophila eye development. BMC Dev Biol 10:28
Li, Wei; Kale, Abhijit; Baker, Nicholas E (2009) Oriented cell division as a response to cell death and cell competition. Curr Biol 19:1821-6
Fullard, John F; Kale, Abhijit; Baker, Nicholas E (2009) Clearance of apoptotic corpses. Apoptosis 14:1029-37
Li, Wei; Baker, Nicholas E (2007) The active role of corpse engulfment pathways during cell competition. Fly (Austin) 1:274-8
Tyler, David M; Baker, Nicholas E (2007) Expanded and fat regulate growth and differentiation in the Drosophila eye through multiple signaling pathways. Dev Biol 305:187-201
Tyler, David M; Li, Wei; Zhuo, Ning et al. (2007) Genes affecting cell competition in Drosophila. Genetics 175:643-57

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