Expression of c-ret promotes morphogenesis and cell survival in mIMCD-3 cells

Dawn A. O'Rourke, Hiroyuki Sakurai, Katherine Spokes, Crystal Kjelsberg, Masahide Takahashi, Sanjay Nigam, Lloyd Cantley

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Abstract

c-Ret, a protein tyrosine kinase receptor, and its ligand glial-derived neurotropic factor (GDNF) are critical for early regulation of ureteric bud development and nephrogenesis. To address whether c-ret directly initiates epithelial cell morphogenesis, the c-ret receptor was expressed in murine inner medullary collecting duct cells (mIMCD-3, a cell line of ureteric bud origin, which has no detectable endogenous c-ret expression). Stable expression of wild-type c-ret was found to yield a constitutively tyrosine- phosphorylated receptor, with no change after the addition of GDNF. Examination of mRNA from these cells demonstrated the message for endogenous GDNF, suggesting that c-ret was potentially being constitutively activated by an autocrine mechanism. When mIMCD-3 cells stably expressing the phosphorylated c-ret receptor were cultured in a type I collagen matrix, they exhibited little GDNF-independent or -dependent branching process formation at early time points compared with the known morphogen hepatocyte growth factor (HGF) (48 h; control, 0.33 ± 0.33; GDNF, 1.0 ± 0.58, P = nonsignificant; and HGF, 6.33 ± 0.33 processes/20 cell clusters, P < 0.001), whereas extended culture (7 days) under serum-free conditions revealed a marked increase in cell survival and the spontaneous development of rudimentary branching process formation. Extended culture (7 days) of c-ret- expressing clones in type I collagen with the epithelial morphogens HGF and/or epidermal growth factor (EGF) resulted in the development of complex three-dimensional spiny cysts, whereas parental mIMCD-3 cells died under these conditions. We conclude that activated c-ret appears to mediate epithelial morphogenesis by prolonging cell survival and, in conjunction with activation of the morphogenic receptors c-met and the EGF receptor, initiates the events required for very early branching morphogenesis.

Original languageEnglish
Pages (from-to)F581-F588
JournalAmerican Journal of Physiology - Renal Physiology
Volume276
Issue number4 45-4
DOIs
Publication statusPublished - 04-1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

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    O'Rourke, D. A., Sakurai, H., Spokes, K., Kjelsberg, C., Takahashi, M., Nigam, S., & Cantley, L. (1999). Expression of c-ret promotes morphogenesis and cell survival in mIMCD-3 cells. American Journal of Physiology - Renal Physiology, 276(4 45-4), F581-F588. https://doi.org/10.1152/ajprenal.1999.276.4.f581