Regulation of Lymphocyte Development by Helix Loop Helix Proteins

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DESCRIPTION (provided by applicant): B lymphocytes, the producers of antibodies, are an essential component of the adaptive immune response. These cells develop from multipotent progenitors through a process that is dependent on the coordinated activity of numerous transcriptional regulatory proteins. However, very little is known about the mechanisms by which these factors control the differentiation process and how their activities are regulated. Mice that lack the transcription factors encoded by the E2A or EBF genes have a profound B cell immune deficiency resulting from the failure to develop cells that are committed to differentiation through the B lymphocyte lineage. The E2A proteins, El2 and E47, are also required for proper T lymphocyte development and to suppress the development of T cell lymphoma. The mechanisms by which the E2A proteins activate B lineage specific gene expression and promote B lineage determination are currently not known (Aim 1). Our preliminary data indicate that EBF is one of the essential targets of E2A that promote B lineage determination. We propose to test the hypothesis that EBF is the major target of E2A required for B lineage commitment (Aim 2). The E2A proteins function at the apex of a transcriptional cascade that culminates in B lineage commitment; however, it is not known how E2A activity is regulated during this process. We hypothesize that altered expression of E2A antagonists, the Id proteins, in lineage-unrestricted progenitors restricts the fate of the developing cell by influencing E2A activity. This hypothesis will be tested using both in vitro and in vivo models of Id gene regulation (Aim3). These studies will lead to a greater understanding of the genetic basis for lineage determination and will provide insight into the essential requirements for proper lymphocyte development.