The long term objective of the research initiated by this proposal is to investigate the genetic regulation of mammalian development. The principal experimental objective is to compile fate maps of the mature fates of cells that descend from progenitors that transiently express specific candidate mammalian developmental control genes during embryonic and fetal stages in transgenic mice. This will be done both in normal mice, and in mice that fail to express the normal products of genes of interest. A novel molecular paradigm for fate mapping will be employed that is based on the precise recombination of transgenes by the yeast recombinase FLP. By this means, the transient activity of a gene can be used to indelibly mark not only the cells in which the gene is expressed, but all of its descendants, even if the latter do not express the gene.
The specific aims of this proposal are to define the descendant domains (lineages) established by progenitors that transiently express Hox 2.9, Krox 20, or Hox 2.6 in the hindbrain and adjacent branchial arch tissues in both normal animals and in, animals that fail to express the normal products of these genes. Both the descendant expression domains and the descendant functional domains of these genes will be mapped and distinguished from one another. The first product of the research program will be a fate map of the mouse that correlates early patterns of gene expression with the organization of cells and tissues in the mature, normal animal. The second product will be a knowledge of whether, and if so how, these fates are altered when the gene of interest is not expressed. They will additionally address the question of compartmentation in the mammalian hindbrain and branchial arches. The maps of normal and mutant cell fates will enormously increase our understanding of the roles played by individual genes in the intricate genetic program that regulates mammalian development, and additionally provide a wealth of new information about cell proliferation, cell mixing, and cell migration in the mammalian embryo. In this manner, the research program will contribute to an improved understanding of normal mammalian development and to the kinds of developmental deficits that arise from alterations in specific gene products.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Salk Institute for Biological Studies
La Jolla
United States
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Rottkamp, Catherine A; Lobur, Katherine J; Wladyka, Cynthia L et al. (2008) Pbx3 is required for normal locomotion and dorsal horn development. Dev Biol 314:23-39
O'Gorman, Stephen (2005) Second branchial arch lineages of the middle ear of wild-type and Hoxa2 mutant mice. Dev Dyn 234:124-31
Guo, Sun-Wei (2002) Sibling recurrence risk ratio as a measure of genetic effect: caveat emptor! Am J Hum Genet 70:818-9