C-KIT AND URETERAL PERISTALSIS

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Abstract
c-kit encodes a tyrosine kinase receptor that is required for the differentiation of a wide variety of cells during embryogenesis, including pacemaker cells of the gut. Functional expression of this tyrosine kinase receptor is required for gut peristalsis and c-kit expression has recently been documented in the adult murine urinary tract. In this study we analyzed the temporal onset of c-kit expression during ureter morphogenesis in vivo and determined if c-kit activity is essential for ureteral peristalsis in vitro. The kidneys and ureters of gestational days 12.5 to 17.5 WT mice were isolated and frozen sections were prepared for analysis of c-kit, α-smooth muscle actin and uroplakin expression by immunocytochemical techniques. In addition, ureters were isolated from gestational day 15.5 mouse urogenital systems and cultured at the air/medium interface on 0.4 um pore polycarbonate membrane filters with Dulbecco's modified Eagle's medium/fetal calf serum in the presence or absence of antibodies that inhibit c-kit function. By gestational day 15.5 c-kit expression could be detected in a subset of renal epithelia and cells of the ureteropelvic adventitia. Prominent staining for c-kit was seen in the muscularis propria of the proximal ureter. In vitro studies demonstrated that isolated embryonic ureters acquire the ability to undergo unidirectional contractions after 3 days of culture, which is coincident with up-regulation of c-kit expression. Furthermore, incubation of isolated ureters with antibodies that neutralize c-kit activity markedly altered ureter morphology and peristalsis. We identified the initial expression and location of c-kit in the embryonic murine upper urinary tract. c-kit expression is up-regulated in the developing ureter prior to the ability of this tissue to undergo unidirectional contractions and c-kit function is required for the peristalsis in vitro.