IQGAP1 promotes early B cell development, is essential for the development of marginal zone (MZ) B cells, and is critical for both T-dependent and T-independent antibody responses.

IQGAP1 is a multi-functional scaffold protein. However, its role in B cell development and function is unknown. Here, we show IQGAP1 as an essential scaffold that regulates early B cell development and function. Iqgap1^-/- mice contained significantly increased numbers of B220⁺ B, B220⁺IgM^- pro/pre-B, and B220^LowIgM⁺ immature-B cells in the bone marrow. In the spleens of the Iqgap1^-/- mice, newly formed and follicular B cell numbers were increased, while the marginal zone B cell numbers were significantly reduced. Lack of IQGAP1 reduced T-dependent and T-independent humoral responses. Mechanistically, the lack of IQGAP1 considerably decreased the phosphorylation of Mek1/2, Erk1/2, and Jnk1/2. B cells from Iqgap1^-/- mice failed to suppress IL-7R-mediated activation of Stat5a/b, an essential step for cell-cycle exit and initiate light-chain recombination, reducing RS rearrangement frequency. Our study provides the first evidence that IQGAP1-based signalosome is necessary for the development and functions of B cells.