Casitas B cell lymphoma (Cbl) proteins are negative regulators for T cell antigen receptor (TCR) signaling. Their role in thymocyte development remains unclear. Here we show that simultaneous inactivation of c-Cbl and Cbl-b in thymocytes enhanced thymic negative selection and altered the ratio of CD4+ and CD8+ T cells. Strikingly, the mutant thymocytes developed into CD4+- and CD8+-lineage T cells independent of the major histocompatibility complex (MHC), indicating that the CD4+- and CD8+-lineage development programs are constitutively active in the absence of c-Cbl and Cbl-b. The mutant double-positive (DP) thymocytes exhibited spontaneous hyperactivation of nuclear factor-kappa B (NF-kB). Additionally, they failed to downregulate the pre-TCR and pre-TCR signaling. Thus, our data indicate that Cbl proteins play a critical role in establishing the MHC-dependent CD4+ and CD8+ T cell development programs. They likely do so by suppressing MHC-independent NF-kB activation, possibly through downmodulating pre-TCR signaling in DP thymocytes.

Transgene insertion is instrumental to identifying genes with defined physiological functions. In this paper, we show that mice homozygous for either TM1 or TM2, two mutant alleles with distinct transgene insertions, exhibited embryo lethality, suggesting that these two alleles play essential roles in embryogenesis. Interestingly, although hemizygous TM1 or TM2 alone did not have obvious alteration in thymocyte development, together, they exhibited a compound effect on thymocyte development, blocking the development from CD4 and CD8 double-negative to double-positive stage of T cells. TM1 and TM-mutations were mapped to chromosome regions 7E-F1 and 11B5-C, respectively, where we could not identify any known gene that was implicated in a similar function. Thus, TM1 and TM2 represent two novel alleles that define a genetic trait controlling thymocyte development.

The newly discovered Cbl-interacting protein of 85 kDa (CIN85) is involved in many cellular processes, but its functions in the brain and in neurodegenerative diseases remain unclear. In this paper, we investigated the distribution of CIN85 protein in different regions of adult mouse brain using Western blot analysis and immunohistochemistry, and found that CIN85 was ubiquitously expressed in mouse brain. In the striatum and substantia nigra, two regions most deeply affected in Parkinson’s disease, the level of CIN85 protein was relatively high. In the MPTP mouse model of Parkinson’s disease, the expression of CIN85 in the striatum and substantia nigra was complicated. But in 1-methyl-4-phenyl-pyridinium ion-treated humandopaminergic SH-SY5Y cells, the expression of CIN85 increased dramatically. Knocking down of CIN85 by short hairpin RNA reduced SH-SY5Y cell death. Therefore, CIN85 might play different roles in the dopaminergic cell line and in the nigrostriatum of mouse brain under neurotoxin challenge.