Secreted Wnt antagonist Dickkopf-1 controls kidney papilla development coordinated by Wnt-7b signalling

Abstract

Wnt signalling regulates several aspects of kidney development such as nephrogenesis, ureteric bud branching and organisation of the collecting duct cells. We addressed the potential involvement of Dickkopf-1 (Dkk1), a secreted Wnt pathway antagonist. Dkk1 is expressed in the developing mouse kidney by pretubular cell aggregates and the nephrons derived from them. Besides the mesenchyme cells, the epithelial ureteric bud and more mature ureteric bud derivatives in the medulla and the papilla tip express the Dkk1 gene. To reveal the potential roles of Dkk1, we generated a floxed allele and used three Cre lines to inactivate Dkk1 function in the developing kidney. Interestingly, Dkk1 deficiency induced by Pax8Cre in the kidneys led in newborn mice to an overgrown papilla that was generated by stimulated proliferation of the collecting duct and loop of Henle cells, implying a role for Dkk1 in the collecting duct and/or loop of Henle development. Since Pax8Cre-induced Dkk1 deficiency reduced marker gene expression, Scnn1b in the collecting duct and Slc12a1 in the loop of Henle, these results together with the extended papilla phenotype are likely reasons for the decreased amount of ions and urine produced by Dkk1-deficient kidneys in the adult. Recombinant Dkk1 protein in cultured cells inhibited Wnt-7b-induced canonical Wnt signalling, which is critical for collecting duct and loop of Henle development. Moreover, Dkk1 deficiency led to an increase in the expression of canonical Wnt signalling of target Lef-1 gene expression in the stromal cells of the developing papilla. Based on the results, we propose that Dkk1 controls the degree of Wnt-7b signalling in the papilla to coordinate kidney organogenesis.

A Comprehensive Overview of Skeletal Phenotypes Associated with Alterations in Wnt/β-catenin Signaling in Humans and Mice

“…Axial compression tests on the ulna show increased mechanical strength in Dkk1 heterozygous mice, with a higher maximum load and energy (109). Dkk1-floxed mice do exist but have not yet been used to assess skeletal phenotypes with bone-specific expression of Cre (242). In opposition to what was seen in the Dkk1 mouse models, deletion of Dkk2 results in osteopenia, with major defects in mineral apposition rates.…”

Development of the kidney medulla

“…In contrast, inactivation of Dickkopf1 (Dkk1), a secreted Wnt antagonist, in the UB lineage in mice leads to overgrowth of the whole papilla resulting from enhanced proliferation of the collecting duct and loop of Henle cells. 29 This effect of absent Dkk1 may be due to induction of Wnt7b signaling from the collecting duct cells to the stroma. 29 The …”

“…29 This effect of absent Dkk1 may be due to induction of Wnt7b signaling from the collecting duct cells to the stroma. 29 The …”

Wnt7b and Its Direct Target p57kip2 in Renal Medulla Development

“…Wnt7b is a Wnt family ligand important for the proper formation of a number of organs and tissues including the placenta, the eye, the bones, the lungs, the kidney, the central nervous system (CNS), neurons, hair, the pancreas, and olfactory receptor neuron axon connectivity. 70,166,[168][169][170][172][173][174][175][176][177][178][179][180][181][182] Notably, Wnt7b has been reported to regulate vasculature development in the eyes, the brain, and the lungs, by different cellular mechanisms. In the eye, it signals to the endothelial cells of the hyaloid vasculature and activates their apoptosis.…”

“…70 Conversely, deletion of canonical Wnt pathway agonist Dkk1 led to increased expression of Lef1 in the interstitium and a longer medulla. 178 Another gene that causes a shorter renal medulla when lost is p57kip2. 117 In…”