Congenital Nephrotic Syndrome in Mice Lacking CD2-Associated Protein

Author:

Shih Neng-Yao1,Li Jun1,Karpitskii Vladimir1,Nguyen Ancho1,Dustin Michael L.1,Kanagawa Osami1,Miner Jeffrey H.2,Shaw Andrey S.1

Affiliation:

1. Center for Immunology and Department of Pathology,

2. Department of Medicine, Renal Division, Washington University, Saint Louis, MO 63110, USA.

Abstract

CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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2. Hybridization with mouse CD2AP cDNA was used to clone a genomic fragment from a 129/SvJ phage library. A 6-kb fragment 5′ of the exon encoding the first SH3 domain was generated by polymerase chain reaction (PCR) with the following primers: 5′-GCGGCCGCTGTATATGATATGAGTACACTGTAG-3′ and 5′-GCGGCCGCACATTCATTACATACTGCATTC3′. After digestion with Not I it was cloned into the Not I site of the targeting vector pTK.NEO.UMS [

3. Reis L. F., Ruffner H., Stark G., Aguet M., Weissman C., EMBO J. 13, 4798 (1994);

4. ]. A 1.1-kb fragment 3′ of the exon encoding the first SH3 domain was generated with the two primers 5′-TAGAACATCGATGTCAAGAAATAAATGCATATG-3′ and 5′-AATCTAATCGATTCCCAGCATCCACAGCTC-3′ and cloned into the Cla I site of the targeting vector.

5. Transfection of RW-4 embryonic stem (ES) cells was performed by the Washington University ES Cell Core. Homologous recombinants were screened by Southern blotting with a 500–base pair fragment (encompassing the Bam HI–Kpn I fragment) generated with the primers 5′-GGATCCCCTGGAGCTGTGGATG-3′ and 5′-GGTACCATTTCCATTTCTGCTAGG-3′ which is external to the 3′ arm of the targeting vector. Three positive clones were identified and two clones were microinjected into C57/Bl6 blastocysts with standard methods [

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