The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects

doi:10.1152/ajprenal.00125.2009

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The instructive role of metanephric mesenchyme in ureteric bud patterning, sculpting, and maturation and its potential ability to buffer ureteric bud branching defects

Mita M. Shah,²^,* James B. Tee,¹^,* Tobias Meyer,¹^,* Catherine Meyer-Schwesinger,¹^,* Yohan Choi,⁴ Derina E. Sweeney,² Thomas F. Gallegos,⁴ Kohei Johkura,² Eran Rosines,⁵ Valentina Kouznetsova,² David W. Rose,² Kevin T. Bush,² Hiroyuki Sakurai,² and Sanjay K. Nigam¹^,2^,3

Departments of ¹ Pediatrics, ; ²Medicine, ; ³Cellular and Molecular Medicine, ; ⁴Biomedical Sciences, and ; ⁵Bioengineering, University of California, San Diego, California

Submitted March 2, 2009 ; accepted in final form August 26, 2009

Kidney organogenesis depends on reciprocal interactions betweenthe ureteric bud (UB) and the metanephric mesenchyme (MM) toform the UB-derived collecting system and MM-derived nephron.With the advent of in vitro systems, it is clear that UB branchingcan occur independently of MM contact; however, little has beendone to detail the role of MM cellular contact in this process.Here, a model system in which the cultured isolated UB is recombinedwith uninduced MM is used to isolate the effects of the MM progenitortissue on the development and maturation of the collecting system.By morphometrics, we demonstrate that cellular contact withthe MM is required for vectorial elongation of stalks and taperingof luminal caliber of UB-derived tubules. Expression analysisof developmentally significant genes indicates the coculturedtissue is most similar to an embryonic day 19 (E19) kidney.The likely major contributor to this is the functional maturationof the collecting duct and proximal nephron segments in theUB-induced MM, as measured by quantitative PCR, of the collectingduct-specific arginine vasopressin receptor and the nephrontubule segment-specific organic anion transporter OAT1, Na-P_itype 2 cotransporter, and Tamm-Horsfall protein gene expressions.However, expression of aquaporin-2 is upregulated similarlyin isolated UB and cocultured tissue, suggesting that some aspectsof functional maturation can occur independently of MM cellularcontact. In addition to its sculpting effects, the MM normalizeda "branchless" UB morphology induced by FGF7 or heregulin inisolated UB culture. The morphological changes induced by theMM were accompanied by a reassignment of GFR ${alpha}$ 1 (a receptor forGDNF) to tips. Such "quality control" by the MM of UB morphologymay provide resiliency to the branching program. This may helpto explain a number of knockout phenotypes in which branchingand/or cystic defects are less impressive than expected. A secondhit in the MM may thus be necessary to make these defects fullyapparent.

kidney development; branching morphogenesis; mesenchymal-to-epithelial transformation; polycystic kidney disease; kidney tissue engineering

Address for reprint requests and other correspondence: S. K. Nigam, Univ. of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0693 (e-mail: snigam{at}ucsd.edu).