Defining the Requirement for ShcA IN Murine B Cell Development

The adaptor protein Shc is phosphorylated downstream of many cell surface receptors, including antigen and cytokine receptors. However, the role of Shc in B cell development has not been addressed. Here, through conditional expression of a dominant negative Shc mutant and conditional loss of Shc protein expression, I tested a role for Shc during early B lymphopoiesis. In chapter III, I identified a requirement for Shc beginning at either the transition from the pre-pro-B to pro-B stage or within the pro-B pool, with a strong reduction in the number of pre-B cells. This developmental defect appeared to be due to increased cell death rather than impaired proliferation. Additional studies in chapter IV suggest a role for Shc in IL-7-dependent signaling in pro-B cells. Shc is phosphorylated in response to IL-7 stimulation in pro-B cells, and pro-B cells from mice with impaired Shc signaling display signs of increased apoptosis. Together, these data suggest a critical role for Shc in early B lymphopoiesis with a requirement in early B cell survival. In addition, I also identify Shc as a required player in signaling downstream of the IL-7 receptor in early B cells.

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