The Wilms tumor gene, Wt1, is critical for mouse spermatogenesis via regulation of sertoli cell polarity and is associated with non-obstructive azoospermia in humans.
Azoospermia is one of the major reproductive disorders which cause male infertility in humans; however, the etiology of this disease is largely unknown. In the present study, six missense mutations of WT1 gene were detected in 529 human patients with non-obstructive azoospermia (NOA), indicating a strong association between WT1 mutation and NOA. The Wilms tumor gene, Wt1, is specifically expressed in Sertoli cells (SCs) which support spermatogenesis. To examine the functions of this gene in spermatogenesis, Wt1 was deleted in adult testis using Wt1(flox) and Cre-ER(TM) mice strains. We found that inactivation of Wt1 resulted in massive germ cell death and only SCs were present in most of the seminiferous tubules which was very similar to NOA in humans. In investigating the potential mechanism for this, histological studies revealed that the blood-testis barrier (BTB) was disrupted in Wt1 deficient testes. In vitro studies demonstrated that Wt1 was essential for cell polarity maintenance in SCs. Further studies found that the expression of cell polarity associated genes (Par6b and E-cadherin) and Wnt signaling genes (Wnt4, Wnt11) were downregulated in Wt1 deficient SCs, and that the expression of Par6b and E-cadherin was regulated by Wnt4. Our findings suggest that Wt1 is important in spermatogenesis by regulating the polarity of SCs via Wnt signaling pathway and that WT1 mutation is one of the genetic causes of NOA in humans.
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Xiao Na
XN
Wang
Ze Song
ZS
Li
Yu
Y
Ren
Tao
T
Jiang
Ya Qing
YQ
Wang
Min
M
Chen
Jun
J
Zhang
Jian Xiu
JX
Hao
Yan Bo
YB
Wang
Ri Na
RN
Sha
Yi
Y
Huang
Xiao
X
Liu
Jing Chu
JC
Hu
Guang Qing
GQ
Sun
Hong Gang
HG
Li
Cheng Liang
CL
Xiong
Jun
J
Xie
Zhi Mao
ZM
Jiang
Zhi Ming
ZM
Cai
Jun
J
Wang
Jian
J
Wang
Vicki
V
Huff
Yao Ting
YT
Gui
Fei
F
Gao
D000818:Animals; D053713:Azoospermia / Q000235:genetics* / Q000473:pathology; D016764:Cell Polarity; D006801:Humans; D007248:Infertility, Male / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D012708:Sertoli Cells / Q000378:metabolism / Q000473:pathology; D013091:Spermatogenesis / Q000235:genetics*; D025721:WT1 Proteins / Q000235:genetics* / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics; D060528:Wnt4 Protein / Q000235:genetics
C555581:WNT4 protein, human; D025721:WT1 Proteins; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D060528:Wnt4 Protein