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The GYF domain protein CD2BP2 is critical for embryogenesis and podocyte function

Item Type:Article
Title:The GYF domain protein CD2BP2 is critical for embryogenesis and podocyte function
Creators Name:Albert, G.I. and Schell, C. and Kirschner, K.M. and Schäfer, S. and Naumann, R. and Müller, A. and Kretz, O. and Kuropka, B. and Girbig, M. and Hübner, N. and Krause, E. and Scholz, H. and Huber, T.B. and Knobeloch, K.P. and Freund, C.
Abstract:Scaffolding proteins play pivotal roles in the assembly of macromolecular machines such as the spliceosome. The adaptor protein CD2BP2, originally identified as a binding partner of the adhesion molecule CD2, is a pre-spliceosomal assembly factor that utilizes its glycine-tyrosine-phenylalanine (GYF) domain to co-localize with spliceosomal proteins. So far, its function in vertebrates is unknown. Using conditional gene targeting in mice, we show that CD2BP2 is crucial for embryogenesis, leading to growth retardation, defects in vascularization, and premature death at embryonic day 10.5 when absent. Ablation of the protein in bone marrow-derived macrophages indicates that CD2BP2 is involved in the alternative splicing of mRNA transcripts from diverse origins. At the molecular level, we identified the phosphatase PP1 to be recruited to the spliceosome via the N-terminus of CD2BP2. Given the strong expression of CD2BP2 in podocytes of the kidney, we use selective depletion of CD2BP2, in combination with next-generation sequencing, to monitor changes in exon usage of genes critical for podocyte functions, including VEGF and actin regulation. CD2BP2-depleted podocytes display foot process effacement, and cause proteinuria and ultimately lethal kidney failure in mice. Collectively, our study defines CD2BP2 as a non-redundant splicing factor essential for embryonic development and podocyte integrity.
Keywords:GYF Domain, CD2BP2, Alternative Splicing, PP1, Podocytes, VEGF, Animals, Mice
Source:Journal of Molecular Cell Biology
Publisher:Oxford University Press
Page Range:402-414
Date:October 2015
Official Publication:https://doi.org/10.1093/jmcb/mjv039
PubMed:View item in PubMed

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