The Spen protein family is found in worms, flies, and mammals, and is implicated in diverse biological processes from embryogenesis to aging. Spen proteins have three N-terminal RNA recognition motifs and a C-terminal SPOC domain. The mammalian Spen proteins Mint and its human ortholog SHARP interact with the Notch-signaling mediator RBP-J as well as Msx2 and several unliganded nuclear hormone receptors, and impart transcription-repressing activity to these molecules by recruiting corepressors through the SPOC domain. Despite these in vitro findings, Mint/SHARP's physiological role is largely unknown, because Mint germline knockouts are embryonic lethal. To analyze Mint/SHARP function in postnatal mice, we created Mint-floxed mice that allow the Cre/loxP-mediated conditional knockout of Mint. We analyzed Mint and RBP-J epistasis during Notch-dependent splenic B-lymphocyte development, and found that Mint suppresses Notch signaling through RBP-J. In addition, Mint deficiency caused severe hypoplasia in postnatal brain, suggesting it may regulate neuronal cell survival.