SIGNAL TRANSDUCTION: REGULATION OF MAMMALIAN DEVELOPMENT

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In every species examined there are major developmental transitions such as fertilization and gastrulation which extensively alter the structure of the egg or embryo. Evidence suggests that these developmental transitions are influenced or regulated by signal transduction events. Mammalian embryogenesis is no exception to this general scenario of regulation through signal transduction, but mammalian embryos are exceptional in that they exhibit unique developmental transitions, specifically embryonic compaction, blastocyst formation, and formation of primitive epithelia in the egg cylinder. The ultimate goal of the research is to identify the intracellular signal transduction events, and their mechanism(s) of action, at the major developmental transitions in order to understand how the egg and embryo are sculpted into a new form. This knowledge will provide a method of assessing developmental failure, or abnormality, such as birth defects as well as provide possible methods of correcting such defects. These studies were not previously possible because the tools and experimental approaches only recently have become available, specifically the development of membrane permeant kinase agonists and antagonists and calcium chelators, as well as kinase reporter dyes, purified preparations of various kinases and their catalytic sub units, and antibodies to various intracellular signal transduction agents. The SPECIFIC AIMS propose investigation of two developmental trafIlsitions, fertilization (an event common to all species) and embryonic compaction (an event unique to mammalian embryogenisis). The proposed studies on the role of intracellular signalling at fertilization are unique in that they propose to examine events subsequent to the rise in intracellular free calcium. For all of the deve!opmental transitions, events are examined at a mechanistic level rather than a descriptive level. Using these tools it is possible to both map the intracellular activity of the signaling agents and to manipulate activation or repression of the signalling agents in the entire embryo or in specific regions of the embryo followed by assessement of their effects on embryogenesis.