GLIAL-CELL-LINE-DERIVED NEUROTROPHIC FACTOR IS REQUIRED FOR BUD INITIATION FROM URETERAL EPITHELIUM

The shapes of different organs can be explained largely by two fundame ntal characteristics of their epithelial rudiments - the pattern of br anching and the rate of proliferation. Glial-cell-line-derived neurotr ophic factor (GDNF) has recently been implicated in the development of metanephric ureteric epithelium (Pichel, J. G., Shen, L., Sheng, H. Z ., Granholm, A.-C., Drago, J., Grinberg, A., Lee, E. J., Huang, S. P., Saarma, M., Hoffer, B.J., Sariola, H. and Westphal, H. (1996). Nature 382, 73-76; Sanchez, M.P., Silos-Santiago, I., Frisen, J., He, B., Li ra, S.A. and Barbacid, M. (1996). Nature 382, 70-73; Vega, Q.C., Worby , C.A., Lechner, M.S., Dixon, J.E. and Dressier, G.R. (1996). Proc. Na t. Acad. Sci. USA 93, 10657-10661). We have analysed the target cells of GDNF and the manner in which it controls ureteric development, and have compared it with other growth factors that have been associated w ith the regulation of branching morphogenesis, namely hepatocyte growt h factor (HGF) and transforming growth factor-beta 1 (TGF beta 1). We show that GDNF binds directly to the tips of ureteric bud branches, an d that it has the ability to promote primary ureteric buds from variou s segments of Wolffian duct and to attract ureteric branches towards t he source of GDNF. It increases cell adhesion, but is not obviously mi togenic for ureteric cells. The data indicate that GDNF is required pr imarily for bud initiation. Comparison of GDNF, HGF and TGF beta 1 sug gests that the latter act later than GDNF, and may represent a partial ly redundant set of mesenchyme-derived growth factors that control ure teric development. Thus, GDNF is the first defined inducer in the embr yonic metanephric kidney.