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

Autor: Yaoting Gui, Zhi Ming Cai, Yanbo Wang, Xiao Na Wang, Jian Wang, Ya Qing Wang, Fei Gao, Vicki Huff, Cheng Liang Xiong, Tao Jiang, Jing Chu Hu, Min Chen, Hong Gang Li, Ri Na Sha, Yu Ren, Ze Song Li, Yi Huang, Jun Wang, Guang Qing Sun, Xiao Liu, Zhi Mao Jiang, Jian Xiu Hao, Jun Zhang, Jun Xie
Přispěvatelé: Hastie, Nicholas
Rok vydání: 2013
Předmět:
Male
Cancer Research
urologic and male genital diseases
medicine.disease_cause
Mice
Wnt4 Protein
WNT4
Cell polarity
2.1 Biological and endogenous factors
Aetiology
Genetics (clinical)
Azoospermia
Mutation
Wnt signaling pathway
Cell Polarity
Sertoli cell
female genital diseases and pregnancy complications
Cell biology
medicine.anatomical_structure
Germ cell
Research Article
congenital
hereditary
and neonatal diseases and abnormalities
medicine.medical_specialty
lcsh:QH426-470
1.1 Normal biological development and functioning
Biology
Clinical Research
Underpinning research
Internal medicine
Genetics
medicine
Animals
Humans
WT1 Proteins
Spermatogenesis
Molecular Biology
Infertility
Male
Ecology
Evolution
Behavior and Systematics
Sertoli Cells
urogenital system
Contraception/Reproduction
fungi
Wilms' tumor
medicine.disease
Wnt Proteins
lcsh:Genetics
Endocrinology
Infertility
Genetics of Disease
Gene Function
Developmental Biology
Zdroj: PLoS genetics, vol 9, iss 8
PLoS Genetics
PLoS Genetics, Vol 9, Iss 8, p e1003645 (2013)
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1003645
Popis: 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.
Author Summary Infertility is one of the most common health problems, affecting about 15% of the couples in the world. In about half of these couples, infertility is related to male reproductive defect. Azoospermia is one of the major causes of male infertility in humans. Previous studies have found that the mutation or deletion of some genes is associated with azoospermia; however, the genetic cause of this remains largely unknown. In the present study, we detected Wt1 missense mutations in men with non-obstructive azoospermia (NOA). An essential function for WT1 in male spermatogenesis was confirmed by the use of a Wt1 conditional knockout mouse strain. Inactivation of Wt1 resulted in germ cell loss in mice, which was similar to NOA in human patients. Our data indicate that WT1 mutation is one genetic cause of male infertility and suggest that WT1 mutational analysis will be useful for diagnosis in a clinical setting.
Databáze: OpenAIRE
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