Developmental biology is defined by the attempt to understand how different cell fates are established in a multicellular organism. Mutations in this process contribute to disease in people. Caenorhabditis elegans offers extraordinarily powerful tools for the identification and analysis of pathways that regulate cell fates, including sophisticated genetics and a known, invariant cell lineage (i.e. the ancestry and fate of every cell is known from the zygote to the adult in a wild type animal, and is the same in essentially every animal). Knowledge of the invariant cell lineage makes it possible to identify and study mutations affecting cell fates at the level of individual cells. My laboratory focuses on how the pattern of cell fates, and particularly of programmed cell deaths, is determined in one tissue of C. elegans, the ventral nerve cord. We have used a combination of genetic screens (both conventional and RNAi-based) and molecular biology to identify genes that regulate the pattern of programmed cell deaths and cell fates in the ventral nerve cord. We are beginning to work out the molecular mechanisms through which these genes act during development of the ventral nerve cord. It is our goal to elucidate the genetic pathways and molecular mechanisms that regulate cell death in C. elegans, and to test whether the mammalian counterparts of these pathways function similarly during the development of cancer.
We have recently shown that mutations in two classical regulators of developmental fates result in an abnormal pattern of cell death in the ventral cord, and that these genes, which encode transcription factors, directly regulate genes in the canonical cell death pathway to determine whether individual cells survive or die. These results support the perhaps surprising hypothesis that ’master regulators’ of cell fates also act as ’micromanagers’ to determine whether individual cells survive or die.
The human counterparts of these genes are mutant in children with leukemia, suggesting that mutations in these genes contribute to leukemogenesis by preventing programmed cell death of lymphoblasts. Indeed, the human counterparts of all three pathways now known to regulate programmed cell death in C. elegans are mutant in cancer, suggesting that analysis of programmed cell death in C. elegans will suggest the mechanisms whereby some mutations contribute to the development of cancer. In the one case that has been investigated, the genetic pathway that prevents programmed cell death in C. elegans is required to prevent apoptosis of the cancerous cells, confirming the value of our approach. We are currently extending our understanding of the regulation of programmed cell death in the ventral nerve cord of C. elegans and beginning our efforts to extend our findings into human cancer cells.
RESEARCH INTERESTS
Developmental regulation of programed cell death and cell lineage
Leukemogenesis and hematopoietic cell lineage
RECENT PUBLICATIONS
Reddien PW, Cameron S and Horvitz HR, "Phagocytosis promotes programmed cell death in C. elegans" Nature, 412:198-202, 2001
Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S and Orkin SH, "The zinc finger transcription factor Gfi-1 is required for neutrophil differentiation and refines the identity of the myeloid lineages" Immunity, 18:109-120, 2003
Saleque S, Cameron S and Orkin SH, "The zinc-finger protooncogene Gfi-1b is essential for development of the erythroid and megakarycoytic lineages" Genes and Development, 16:301-306, 2001
McLaughlin M, Robson CD, Kieran MW, Jacks T, Pomeroy SL and Cameron S, "Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): A case report and laboratory investigation" J Pedi Hem Oncol, 25:644-648, August 2003
Cameron S, Clark S, McDermott JB, Aamodt E and Horvitz HR, "PAG-3, a Zn finger transcription factor, determines neuroblast fate in C. elegans" Development, 129:1763-1774, 2002
SIGNIFICANT PUBLICATIONS
Cameron S, Clark S, McDermott JB, Aamodt E and Horvitz HR, "PAG-3, a Zn finger transcription factor, determines neuroblast fate in C. elegans" Development, 129:1763-1774, 2002
Saleque S, Cameron S and Orkin SH, "The zinc-finger protooncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages" Genes and Development, 16:301-306, 2001
Hock H, Hamblen MJ, Rooke HM, Traver D, Bronson RT, Cameron S and Orkin SH, "The zinc finger transcription factor Gfi-1 is required for neutrophil differentiation and refines the identity of the myeloid lineages" Immunity, 18:109-120, 2003
Reddien PW, Cameron S and Horvitz HR, "Phagocytosis promotes programmed cell death in C. elegans" Nature, 412:198-202, 2001
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