S-4-4 Role of Ret/GDNF in branching morphogenesis of the ureteric bud
Costantini F., Shakya R., Watanabe T., Srinivas S., D'Agati V., DeGraaff E., Pachnis V.
Organogenesis of the kidney is orchestrated by inductive interactions between the ureteric bud (UB) and the metanephric mesenchyme. One signaling system critical for the growth and branching of the UB involves GDNF secreted by the mesenchyme, and the receptor tyrosine kinase RET and co-receptor GFRal expressed in the UB. We have used a number of approaches to investigate the role of this signaling system in the control of UB growth and branching. Ectopic expression of GDNF in the ureteric bud, or expression of ligand-independent forms of RET, result in abnormally branched, cystic and hyperplastic collecting ducts, suggesting that the orderly growth and branching of the UB are normally regulated by the spatially regulated distributions of RET and GDNF. To examine the role of GDNF localization in outgrowth of the ureteric bud from the Wolffian duct, we developed mice in which the ectopic expression of GDNF is controlled by administration of Doxycycline. Our results support the model that GDNF restricts the outgrowth of the ureteric bud to the caudal-most region of the Wolffian duct. The role of Ret signaling in UB growth is being further investigated through time-lapse imaging of kidney development in organ culture. Other studies have addressed the role the two major isoforms, Ret9 and Ret51, which differ only in their C- terminal tails. Transgenic rescue studies and knock-in experiments show that Ret9 is necessary and sufficient for kidney development, and suggest that Ret51 plays a role in the outgrowth of the ureteric bud and early branching events. © 2002, Japanese Society of Nephrology. All rights reserved.