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2014 ; 23
(25
): 6807-14
Nephropedia Template TP
Yun K
; Ajima R
; Sharma N
; Costantini F
; Mackem S
; Lewandoski M
; Yamaguchi TP
; Perantoni AO
Hum Mol Genet
2014[Dec]; 23
(25
): 6807-14
PMID25082826
show ga
Congenital anomalies of the kidney and urinary tract (CAKUT) affect about 1 in
500 births and are a major cause of morbidity in infants. Duplex collecting
systems rank among the most common abnormalities of CAKUT, but the molecular
basis for this defect is poorly understood. In mice, conditional deletion of
Wnt5a in mesoderm results in bilateral duplex kidney and ureter formation. The
ureteric buds (UBs) in mutants emerge as doublets from the intermediate mesoderm
(IM)-derived nephric duct (ND) without anterior expansion of the glial cell
line-derived neurotrophic factor (Gdnf) expression domain in the surrounding
mesenchyme. Wnt5a is normally expressed in a graded manner at the posterior end
of the IM, but its expression is down-regulated prior to UB outgrowth at E10.5.
Furthermore, ablation of Wnt5a in the mesoderm with an inducible Cre at E7.5
results in duplex UBs, whereas ablation at E8.5 yields normal UB outgrowth,
demonstrating that Wnt5a functions in IM development well before the formation of
the metanephros. In mutants, the posterior ND is duplicated and surrounding
Pax2-positive mesenchymal cells persist in the nephric cord, suggesting that
disruption of normal ND patterning prompts the formation of duplex ureters and
kidneys. Ror2 homozygous mutants, which infrequently yield duplex collecting
systems, show a dramatic increase in incidence with the additional deletion of
one copy of Wnt5a, implicating this receptor in non-canonical Wnt5a signaling
during IM development. This work provides the first evidence of a role of
Wnt5a/Ror2 signaling in IM extension and offers new insights into the etiology of
CAKUT and possible involvement of Wnt5a/Ror2 mutations.