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Dev Biol April 1, 2013; 376 (1): 31-42.

Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros.

Zhang B , Romaker D , Ferrell N , Wessely O .

In the kidney, proximal tubules are very important for the reabsorption of water, ions and organic solutes from the primary urine. They are composed of highly specialized epithelial cells that are characterized by an elaborate apical brush border to increase transport efficiency. Using the pronephric kidney of Xenopus laevis we discovered that the G-protein modulator cholera toxin resulted in a dramatic reduction of the proximal tubular size. This phenotype was accompanied by changes in the cytoarchitecture characterized by ectopic expression of the distal tubular marker 4A6 and an impairment of yolk platelet degradation. In addition, cholera toxin caused edema formation. However, this phenotype was not due to kidney defects, but rather due to impaired vasculature development. Based on experiments with antisense morpholino oligomers as well as pharmacological agonists and antagonists, we could show that the complex phenotype of cholera toxin in the pronephric kidney was caused by the hyperactivation of a single G-protein alpha subunit, Gnas. This-in turn-caused elevated cAMP levels, triggered a Rapgef4-dependent signaling cassette and perturbed exo- and endocytosis. This perturbation of the secretory pathway by Ctx was not only observed in Xenopus embryos. Also, in a human proximal tubular cell line, cholera toxin or a Rapgef4-specific agonist increased uptake and decreased secretion of FITC-labeled Albumin. Based on these data we propose that the Gnas/cAMP/Rapgef4 pathway regulates the signals inducing the proliferation of proximal tubules to acquire their final organ size.

PubMed ID: 23352791
PMC ID: PMC3767149
Article link: Dev Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aplnr atp1a1 elavl1 gnal gnas nphs1 rapgef3 rapgef4 serpina6 slc12a1 slc12a3 slc25a10 slc5a9 slc7a13 slc7a7 smo vsig1
GO keywords: exocytosis [+]
Morpholinos: gnal MO1 gnas MO1 rapgef4 MO1

Article Images: [+] show captions
References [+] :
Adams, Inverse drug screens: a rapid and inexpensive method for implicating molecular targets. 2006, Pubmed