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Ectopic expression of the homeobox gene Cux‐1 rescues calcineurin inhibition in mouse embryonic kidney cultures
Author(s) -
Alcalay Neal I.,
Brantley Jennifer G.,
Sharma Madhulika,
Gooch Jennifer L.,
Vanden Heuvel Gregory B.
Publication year - 2007
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.21003
Subject(s) - biology , ectopic expression , kidney development , microbiology and biotechnology , transgene , calcineurin , cell growth , kidney , kinase , transplantation , embryonic stem cell , cancer research , medicine , endocrinology , cell culture , gene , biochemistry , genetics
Cux‐1 is a murine homeobox gene structurally related to Drosophila cut. Cux‐1 is highly expressed in the nephrogenic zone of the developing kidney, where its expression coincides with cell proliferation. Cux‐1 functions as a transcriptional repressor of the cyclin kinase inhibitors (CKI) p21 and p27. Cux‐1 DNA binding activity is negatively regulated by phosphorylation, and dephosphorylation of Cux‐1 results in increased DNA binding. Transgenic mice ectopically expressing Cux‐1 develop renal hyperplasia associated with the down‐regulation of the CKI p27. Calcineurin A (CnA) α (−/−) mice display renal hypoplasia associated with the ectopic expression of p27. CnA is a serine/threonine phosphatase activated by intracellular calcium. Inhibiting CnA with cyclosporin A (CsA) leads to nephron deficit in rat metanephric organ cultures and apoptosis in various renal cell lines. To determine whether the ectopic expression of p27 in CnA‐α −/− kidneys results from the down‐regulation of Cux‐1, metanephroi from embryonic Cux‐1 transgenic and wild‐type mice were harvested and cultured with CsA for 5 days. CsA treatment significantly inhibited growth of wild‐type metanephroi. In contrast, CsA‐treated Cux‐1 transgenic kidney cultures were not growth inhibited, but showed high levels of cell proliferation in the nephrogenic zone. Moreover, in CsA‐treated Cux‐1 transgenic kidney cultures, p27 was not expressed in the nephrogenic zone, but only up‐regulated in maturing glomeruli and tubules. Taken together, our results demonstrate that ectopic expression of Cux‐1 can rescue the effects of CsA inhibition of CnA and suggest that Cux‐1 may be regulated by calcineurin A. Developmental Dynamics 236:184–191, 2007. © 2006 Wiley‐Liss, Inc.