Nephron endowment in glial cell line-derived neurotrophic factor (GDNF) heterozygous mice.
BACKGROUND
The exact molecular mechanisms that regulate ureteric branching morphogenesis in the developing metanephros have not been fully elucidated. However, in vivo and in vitro evidence indicates that glial cell line-derived neurotrophic factor (GDNF) is a key regulator of the initiation of ureteric branching. GDNF knockout mice show renal agenesis or severe dysgenesis and die 24 hours after birth from renal failure. Inhibition of GDNF activity in metanephric organ culture inhibits ureteric branching. Since nephron initiation only occurs at the tips of ureteric branches, the aim of the present study was to determine whether nephron number in GDNF heterozygous mice is reduced.


METHODS
Male GDNF heterozygous mice of hybrid 129/Sv and C57/BL genetic background were mated with C57BL/6 females. Offspring were genotyped at postnatal day 30 (PN30) by polymerase chain reaction. Left kidneys were used for estimating kidney volume and total nephron number. We also estimated absolute and relative volumes of ureteric duct epithelium. Unbiased stereological methods were used throughout (Cavalieri method, physical disector/fractionator combination).


RESULTS
GDNF wild-type and heterozygous mice had similar body weights at PN30. However, heterozygous kidneys were 25% smaller than wild-type kidneys (wild-type, 114.75 +/- 16.46 mm3; heterozygous, 87.11 +/- 21.84 mm3, P < 0.001) and contained approximately 30% fewer nephrons (wild-type, 11886 +/- 1277; heterozygous, 8573 +/- 2240, P < 0.01). In addition, the absolute ureteric duct volume was significantly reduced in heterozygous mice (P < 0.001).


CONCLUSIONS
: These results indicate that the loss of one GDNF allele results in reduced nephron endowment in the adult kidney, presumably as the result of reduced branching morphogenesis of the ureteric bud.
Cullen-McEwen
L A
LA
Department of Anatomy and Cell Biology, Department of Medicine, Monash University, Clayton, Victoria, Australia.
Drago
J
J
Bertram
J F
JF
D000483:Alleles; D000818:Animals; D005260:Female; D017353:Gene Deletion; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006579:Heterozygote; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D008817:Mice, Mutant Strains / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D009399:Nephrons / Q000473:pathology*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009929:Organ Size / Q000235:genetics; D012016:Reference Values; D014513:Ureter / Q000473:pathology
C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins