The GYF domain protein CD2BP2 plays a crucial role in alternative splicing, embryonic development and podocyte integrity

The spliceosome is a multimolecular ribonucleoprotein complex, which catalyzes the removal of introns from pre-mRNA and extends the complexity of genetic information by defining alternative transcripts. Here we analyzed the in vivo function of CD2BP2, which is a marker of early spliceosomal complexes. Using gene targeting in mice, we show that constitutive or mesoderm- specific ablation of the CD2BP2 gene causes embryonic lethality by E10.5 associated with delayed development, growth retardation and pericard effusion. Transcriptome analysis in CD2BP2 deficient bone-marrow-derived macrophages (BMM) and podocytes revealed dramatic alterations in the alternative splicing pattern of several mRNAs including VEGFA. Consistent with a previously described critical role of specific VEGFA isoforms for podocyte integrity, mice, which specifically lack CD2BP2flox/flox in this cell type, develop progressive albuminuria followed by lethal kidney failure. We further identified the phosphatase PP1 as a GYF domain independent CD2BP2 interaction partner, suggesting that CD2BP2 acts as an important modulator for spliceosome dephosphorylation, thereby affecting alternative splicing of physiologically highly relevant transcripts. Overall design: 3x KO vs 3x WT mus m.