Deficient Expression of Genes Involved in the Endogenous Defense System against Transposons in Cryptorchid Boys with Impaired Mini-Puberty

Hadžiselimović, Faruk; Hadziselimovic, Nils; Demougin, Philippe; Krey, Gunthild; Oakeley, E. J.

doi:10.1159/000335188

Cited by 29 publications

(25 citation statements)

References 66 publications

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“…It is postulated that sterility is most likely caused by the occurrence of double-strand DNA breaks generated by transposition events [Klattenhoff et al, 2007]. In a previous study, we found impaired expression of DDX4 , MAEL , MOV10L1 , PIWIL2 , PIWIL4 , and TDRD9 genes in boys with cryptorchidism, who exhibited a high infertility risk (HIR) due to altered mini-puberty function [Hadziselimovic et al, 2011a]. That finding indicated that gene instability is induced by impairment in the endogenous system that defends against transposons; we hypothesized that this instability may contribute to the development of azoospermia.…”

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confidence: 76%

Piwi-Pathway Alteration Induces LINE-1 Transposon Derepression and Infertility Development in Cryptorchidism

Hadžiselimović¹,

Hadziselimovic

Demougin

et al. 2015

Sex Dev

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Spermatogonia contain processing bodies that harbor P-element-induced wimpy testis (Piwi) proteins. Piwi proteins are associated specifically with Piwi-interacting RNAs to silence transposable DNA elements. Loss-of-function mutations in the Piwi pathway lead to derepression of transposable elements, resulting in defective spermatogenesis. Furthermore, deletion of gametocyte-specific factor 1 (GTSF1), a factor involved in Piwi-mediated transcriptional repression, causes male-specific sterility and derepression of LINE-1 (L1) retrotransposons. No previous studies have examined GTSF1, L1 and PIWIL4 expression in cryptorchidism. We examined transposon-silencing genes and L1 transposon expression in testicular biopsies with Affymetrix microarrays and immunohistology. Seven members of the Tudor gene family, 3 members of the DEAD-box RNA helicase family, and the GTSF1 gene were found to show significantly lower RNA signals in the high-infertility-risk group. In the immunohistochemical analysis, patients from the low-infertility-risk group showed coherently stronger staining for GTSF1 and PIWIL4 proteins and weaker staining for L1 transposon when compared to the high-infertility-risk samples. These new findings provide first evidence consistent with the idea that infertility in cryptorchidism is a consequence of alterations in the Piwi pathway and transposon derepression induced by the impaired function of mini-puberty.

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confidence: 76%

Piwi-Pathway Alteration Induces LINE-1 Transposon Derepression and Infertility Development in Cryptorchidism

Hadžiselimović¹,

Hadziselimovic

Demougin

et al. 2015

Sex Dev

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“…Thus, on the basis of the reviewed evidence, it can be proposed that piRNAs play much broader roles than it have been previously appreciated. A study by Hadziselimovic et al (2011) reported the lack of expression of MOV10L1 in cryptorchid boys at high risk of developing azoospermia. The lower level of testosterone and free-androgen was observed in cryptorchid infants, indicating insufficient gonadotropin and testosterone stimulation (Pierik et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…The importance of MOV10L1 has been documented in patients at risk of azoospermia. In the group of cryptorchid boys at high risk of infertility, the expression of DDX4, MAEL, MOV10L1, PIWIL2, PIWIL4, and TDRD9 was impaired, which indicated that gene instability induced by impaired expression of transposon silencing genes contribute to the development of azoospermia (Hadziselimovic et al 2011). The MOV10L1 gene is thus named because it is homologous to MOV10.…”

Section: Role Of Mov10l1mentioning

confidence: 99%

MOV10L1 in piRNA processing and gene silencing of retrotransposons during spermatogenesis

Zhu

Zhi

2015

Reproduction

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Piwi-interacting RNAs (piRNAs) are a broad group of non-coding small RNAs with important biological functions in germline cells. It is well known that piRNAs can maintain genome integrity via silencing retrotransposons. Previous studies on the animal models harboring gene deletions have shown that the genes involved in piRNA biogenesis and their defective expression can result in the spermatogenic dysfunction. In the past decade, significant progress has been achieved for piRNAs and their roles in male germ cells. This review addresses the advances on piRNAs and piRNA biogenesis-associated genes, with a particular focus on the Moloney leukemia virus 10-like 1 (MOV10L1) gene, whose role in primary piRNA processing and in the 'ping-pong' cycle during secondary piRNA processing has been illustrated. The biological characteristics of piRNA has been summarized, and emphasis was laid on the roles of MOV10L1 in the mediation of piRNA biogenesis and retrotransposons silencing by DNA methylation. Furthermore, the association between MOV10L1 gene polymorphisms and complete maturation arrest in men has been discussed. Hence, thorough literature review was conducted in order to obtain a greater understanding of the function of MOV10L1 and its mechanisms underlying spermatogenesis in mice and humans. Free Chinese abstract: A Chinese translation of this abstract is freely available at

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“…This suggests that gene instability induced by impaired expression of transposon-silencing genes may have contributed to the development of azoospermia. Intact mini-puberty appeared to be essential for the development of the endogenous defense system mediated by transposon silencing [25]. …”

Section: Role Of Temperaturementioning

confidence: 99%

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

Hadžiselimović¹

2016

Urol Int

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The ultimate goal in the treatment of cryptorchidism is to achieve normal fertility. However, in a substantial number of cryptorchid males, early and apparently successful orchidopexy does not improve fertility as it does not address the underlying pathophysiological cause, namely, the impaired transformation of gonocytes into Ad spermatogonia. It is important to realize that over half the patients presenting with unilateral cryptorchidism and the majority of those presenting with bilateral cryptorchidism have abnormal spermiogram which indicates that unilateral cryptorchidism is in fact a bilateral disease and therefore a serious andrological problem. More importantly, only testicular biopsy can nowadays determine which patient should benefit from hormonal therapy. This means that the rationale behind testicular biopsy is both diagnostic and therapeutic, particularly since LH-RHa hormonal therapy is a worthwhile solution to this andrological problem. In boys with a high risk of azoospermia development, adequate treatment with low doses of LH-RHa allowed 86% of subjects to achieve a normal sperm count. This strongly contrasts with the results of the ‘surgery-only' group where not a single patient had a normal spermiogram and 20% suffered from azoospermia. Testicular biopsy is all the more justified that it allowed the detection of in situ carcinoma in 0.6% of all the cryptorchid boys studied. Even if hormonal pre-treatment only achieves successful epididymo-testicular descent in 20% of cases, this treatment should remain the first therapeutic choice because it may avoid resorting to surgery. In addition, it has no adverse effect on fertility and, in unsuccessful cases, facilitates orchidopexy and considerably helps reduce the incidence of post-surgical testicular atrophy, whether unilateral or, and this is a much more serious event, bilateral.

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Deficient Expression of Genes Involved in the Endogenous Defense System against Transposons in Cryptorchid Boys with Impaired Mini-Puberty

Cited by 29 publications

References 66 publications

Piwi-Pathway Alteration Induces LINE-1 Transposon Derepression and Infertility Development in Cryptorchidism

Piwi-Pathway Alteration Induces LINE-1 Transposon Derepression and Infertility Development in Cryptorchidism

MOV10L1 in piRNA processing and gene silencing of retrotransposons during spermatogenesis

Opinion: Comment on Evaluation and Treatment of Cryptorchidism: AUA/AAP and Nordic Consensus Guidelines

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