ESPN 50th Annual Meeting

ESPN 2017


 
GDNF controls ureter length by regulating collecting duct progenitor expansion
Hao Li 1 Madis Jakobson 1 Roxana Ola 2 Hannu Sariola 1 Jaan-Olle Andressoo 1 Satu Kuure 1

1- University of Helsinki
2- Yale University
 
Introduction:

Mechanisms controlling ureter length and kidney position in the abdominal cavity are poorly understood. Signaling through RET tyrosine kinase receptor is important for urogenital system (kidneys, associated urine excretion organs and reproductive organs) development, but which of its four ligands is involved in specific processes remains unclear.

Material and methods:

We have studied how glial cell-line derived neurotrophic factor (GDNF) impacts the patterning of the whole urogenital system by utilizing a new mouse model endogenously expressing excess GDNF due to disruption of normal 3’untranslated region function. These hypermorphic GDNF mice develop hypodysplastic kidneys and survive approximately two weeks after birth.

Results:

We show that GDNF regulates collecting duct progenitors, a newly identified cell population residing in the ureteric bud tips. High GDNF levels expand progenitors at the expense of ureteric trunk elongation due to changes in cell cycle length and progenitor motility. Consequently kidneys fail to ascend to their normal position resembling human pelvic kidneys. Interestingly, postnatal nephrogenesis continues longer in GDNF hypermorphic kidneys than in control mice, suggesting that GDNF could act as a cessation signal for renal differentiation. Furthermore, normal GDNF level is also important for distal ureter remodeling as excess GDNF leads to infertility in both genders due to an imperforate hymen in females and due to an ectopic connection of vas deferens to seminal vesicles in males.

Conclusions:

Our findings show that GDNF plays several functions beyond ureteric bud induction and suggest that abnormal GDNF levels may be causative for a portion of CAKUT, pelvic kidney and infertility cases in humans.