Expression of the Ubiquitin Proteasome System in Neonatal Rat Gonocytes and Spermatogonia: Role in Gonocyte Differentiation1

Manku, Gurpreet; Wing, Simon S.; Culty, Martine

doi:10.1095/biolreprod.112.099143

Cited by 33 publications

(56 citation statements)

References 73 publications

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“…Another system that plays a role in gonocyte differentiation is the ubiquitin-proteasome system (UPS), as revealed by studies where we have demonstrated that inhibiting proteasome activation with the specific inhibitors lactacystin and bortezomib significantly decreased the RA-driven induction of Stra8 expression in rat gonocytes (Manku et al 2012). In this study, we also identified several UPS proteins preferentially expressed in gonocytes, such as the E3 ligase RNF149, that might have a role in gonocyte development.…”

Section: Transitional Gonocyte Differentiation In Rodentsmentioning

confidence: 58%

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Manku¹,

Culty²

2015

Reproduction

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123

105

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The production of spermatozoa relies on a pool of spermatogonial stem cells (SSCs), formed in infancy from the differentiation of their precursor cells, the gonocytes. Throughout adult life, SSCs will either self-renew or differentiate, in order to maintain a stem cell reserve while providing cells to the spermatogenic cycle. By contrast, gonocytes represent a transient and finite phase of development leading to the formation of SSCs or spermatogonia of the first spermatogenic wave. Gonocyte development involves phases of quiescence, cell proliferation, migration, and differentiation. Spermatogonia, on the other hand, remain located at the basement membrane of the seminiferous tubules throughout their successive phases of proliferation and differentiation. Apoptosis is an integral part of both developmental phases, allowing for the removal of defective cells and the maintenance of proper germ-Sertoli cell ratios. While gonocytes and spermatogonia mitosis are regulated by distinct factors, they both undergo differentiation in response to retinoic acid. In contrast to postpubertal spermatogenesis, the early steps of germ cell development have only recently attracted attention, unveiling genes and pathways regulating SSC self-renewal and proliferation. Yet, less is known on the mechanisms regulating differentiation. The processes leading from gonocytes to spermatogonia have been seldom investigated. While the formation of abnormal gonocytes or SSCs could lead to infertility, defective gonocyte differentiation might be at the origin of testicular germ cell tumors. Thus, it is important to better understand the molecular mechanisms regulating these processes. This review summarizes and compares the present knowledge on the mechanisms regulating mammalian gonocyte and spermatogonial differentiation.

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Section: Transitional Gonocyte Differentiation In Rodentsmentioning

confidence: 58%

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Manku¹,

Culty²

2015

Reproduction

Self Cite

123

105

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“…Recently, Manku and colleagues demonstrated that bortezomib blocks the ability of retinoic acid to increase the expression of differentiating spermatogonial markers Stra8 and Dazl in gonocytes isolated from testes of postnatal day 3 rats [25]. Differentiation of neonatal testicular gonacytes to spermatogonia is a critical step for the establishing of the spermatogonial stem cell population, a crucial point for future fertility.…”

Section: Discussionmentioning

confidence: 99%

Bortezomib treatment causes long-term testicular dysfunction in young male mice

et al. 2014

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BackgroundWith increased long-term survivors of childhood cancer patients, therapy-associated infertility has become one of the most common late side-effects and significantly affects their life-quality. Therefore, evaluation of anti-cancer agents on male reproduction and infertility prevention are urgently demanding. The proteasome inhibitor bortezomib has been launched in clinical trials for childhood cancers, however, its potential side effects on reproduction have so far been neither investigated experimentally nor reported in treated children. Thus the present study is designed to explore the impact of bortezomib on male reproductive function and to gain insights into how bortezomib exerts its adverse effects on man gonad, thereby providing pediatric oncologists relevant information.Methods35 day-old male mice were treated with one 11-day cycle of bortezomib and then sacrificed 2 days, 45 days, or 6 months later. A mating study was performed in the group followed for 6 months, and their pups were analyzed on postnatal day 50. Serum follicle-stimulating hormone (FSH) and testicular testosterone levels were measured. Testicular morphology was evaluated by light- and electron microscopy, and the underlying mechanisms and pathways of testis damage were investigated.ResultsTesticular damage was visible already 2 days after stopping bortezomib and increased in severity by day 45. Then 80% of seminiferous tubules exhibited hypospermatogenesis with arrest at the levels of spermatogonia, spermatocytes and round spermatids. Germ cells were specifically targeted by bortezomib as evidenced by increased apoptosis mediated through activation of p53 and caspases. Even six months after the bortezomib treatment, testis weight, sperm concentration and seminiferous tubule length remained at a decreased level, indicating that spermatogenesis and tubular outgrowth could not fully recover. Combined with persistently increased serum levels of FSH in these mice, our results demonstrate that bortezomib can have long-term effects on testicular function, although fertility of bortezomib-exposed males remained and their offspring looked healthy.ConclusionBortezomib treatment causes long-term gonadal dysfunction in male mice. Careful monitoring of gonadal function in male childhood cancer patients treated with bortezomib is thus strongly recommended.

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“…For example, the specific E2 conjugating enzyme UBC4 has been shown to be necessary for functional spermatogenesis in mice [27] and the importance of the deubiquitinating enzyme, UCH-L1, that regenerates mono-ubiquitin from ubiquitin-protein complexes, is highly expressed in spermatogonia [28–33]. A comprehensive analysis of genes of the UPS in neonatal rat gonocytes and spermatogonia has identified a number of novel ubiquitin-related genes specific to these cells [17]. The intent of this section is to provide examples that illustrate the participation of specific E3 ubiquitin ligases in the regulation of spermatogenesis.…”

Section: Known Testicular E3 Ligases and Their Influence On Spermamentioning

confidence: 99%

“…The outer two α subunits serve to regulate the entry of proteins at either end of the cylinder by binding to one of the two regulatory caps (also know as regulatory particles) that recognize specific polyubiquitin chains and promote the entry of the protein into the cylinder and its subsequent degradation by the proteases within. Alterations in UPS-associated genes have been correlated with male infertility, signifying a critical role for the UPS in functional adult spermatogenesis [17]. Furthermore, a tissue specific proteasome subtype has been identified in the testis and is described in detail below.…”

Section: Introductionmentioning

confidence: 99%

The role of E3 ligases in the ubiquitin-dependent regulation of spermatogenesis

Richburg

Myers

Bratton

2014

Seminars in Cell & Developmental Biology

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The ubiquitination of proteins is a post-translational modification that was first described as a means to target misfolded or unwanted proteins for degradation by the proteasome. It is now appreciated that the ubiquitination of proteins also serves as a mechanism to modify protein function and cellular functions such as protein trafficking, cell signaling, DNA repair, chromatin modifications, cell-cycle progression and cell death. The ubiquitination of proteins occurs through the hierarchal transfer of ubiquitin from an E1 ubiquitin-activating enzyme to an E2 ubiquitin-conjugating enzyme and finally to an E3 ubiquitin ligase that transfers the ubiquitin to its target protein. It is the final E3 ubiquitin ligase that confers the substrate specificity for ubiquitination and is the focus of this review. Spermatogenesis is a complex and highly regulated process by which spermatogonial stem cells undergo mitotic proliferation and expansion of the diploid spermatogonial population, differentiate into spermatocytes and progress through two meiotic divisions to produce haploid spermatids that proceed through a final morphogenesis to generate mature spermatozoa. The ubiquitination of proteins in the cells of the testis occurs in many of the processes required for the progression of mature spermatozoa. Since it is the E3 ubiquitin ligase that recognizes the target protein and provides the specificity and selectivity for ubiquitination, this review highlights known examples of E3 ligases in the testis and the differing roles that they play in maintaining functional spermatogenesis.

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Expression of the Ubiquitin Proteasome System in Neonatal Rat Gonocytes and Spermatogonia: Role in Gonocyte Differentiation1

Cited by 33 publications

References 73 publications

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Bortezomib treatment causes long-term testicular dysfunction in young male mice

The role of E3 ligases in the ubiquitin-dependent regulation of spermatogenesis

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