Abstract
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 Wt1flox and Cre-ERTM 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.
Highlights
IntroductionAbout 50% are related to male infertility [1], a major cause of which is azoospermia
Infertility is a common health problem which affects about 15– 20% of couples
Previous studies have found that the mutation or deletion of some genes is associated with azoospermia; the genetic cause of this remains largely unknown
Summary
About 50% are related to male infertility [1], a major cause of which is azoospermia. Genetic causes of azoospermia include autosomal chromosome abnormalities, Y chromosome microdeletions, and single gene mutations. Several genes have been reported to play a role in azoospermia, including PRM1, SPATA16, AURKC, and KLHL10 [2,3,4,5]. Sertoli cell (SCs) play central roles in testis development and spermatogenesis. Mammalian spermatogenesis is dependent on the proper functioning of SCs which provide structural support and nutrition to developing germ cells, phagocytose degenerating germ cells and residual bodies, release spermatids at spermiation, and produce a host of proteins that regulate or respond to pituitary hormone [8,9,10]
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