Regulated expression of the ubiquitin protein ligase, E3<sup>Histone</sup>/LASU1/Mule/ARF‐BP1/HUWE1, during spermatogenesis

Liu, Zhiqian; Miao, Dengsheng; Xia, Qingwen; Hermo, Louis; Wing, Simon S.

doi:10.1002/dvdy.21302

Cited by 43 publications

(36 citation statements)

References 45 publications

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“…The E3 ligase Trim28 (TIF1b), abundant in germ and somatic cells, was also shown to affect chromatin structure [46] and to be a transcriptional corepressor required for proper spermatogenesis [47]. Similarly, HUWE1 (ARF-BP1; LASU1), corresponding to the most abundant E3 ligase transcript in gonocytes, is highly expressed in the nuclei of spermatogonia and spermatocytes and was shown to poly-ubiquitinate histones in vitro [28] and was proposed to play a role in histone removal during chromatin condensation in elongating spermatids [48]. However, the localization of Huwe1 in gonocyte cytoplasm and in cytoplasmic extensions of germ cells making contact with the basement membrane of the seminiferous cords suggest that Huwe1 has a distinct role unrelated to chromatin remodeling at this stage of germ cell development.…”

Section: Ubiquitin System In Gonocyte Differentiationmentioning

confidence: 97%

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

Manku

Wing

Culty

2012

Biology of Reproduction

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The ubiquitin proteasome system (UPS) consists of a cascade of enzymatic reactions leading to the ubiquitination of proteins, with consequent degradation or altered functions of the proteins. Alterations in UPS genes have been associated with male infertility, suggesting the role of UPS in spermatogenesis. In the present study, we questioned whether UPS is involved in extensive remodeling and functional changes occurring during the differentiation of neonatal testicular gonocytes to spermatogonia, a step critical for the establishment of the spermatogonial stem cell population. We found that addition of the proteasome inhibitor lactacystin to isolated gonocytes inhibited their retinoic acid-induced differentiation in a dose-dependent manner, blocking the induction of the spermatogonial gene markers Stra8 and Dazl. We then compared the UPS gene expression profiles of Postnatal Day (PND) 3 gonocytes and PND8 spermatogonia, using gene expression arrays and quantitative real-time PCR analyses. We identified 205 UPS genes, including 91 genes expressed at relatively high levels. From those, 28 genes were differentially expressed between gonocytes and spermatogonia. While ubiquitin-activating enzymes and ligases showed higher expression in gonocytes, most ubiquitin conjugating and deubiquitinating enzymes were expressed at higher levels in spermatogonia. Concomitant with the induction of spermatogonial gene markers, retinoic acid altered the expression of many UPS genes, suggesting that the UPS is remodeled during gonocyte differentiation. In conclusion, these studies identified novel ubiquitin-related genes in gonocytes and spermatogonia and revealed that proteasome function is involved in gonocyte differentiation. Considering the multiple roles of the UPS, it will be important to determine which UPS genes direct substrates to the proteasome and which are involved in proteasome-independent functions in gonocytes and to identify their target proteins.

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Section: Ubiquitin System In Gonocyte Differentiationmentioning

confidence: 97%

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

Manku

Wing

Culty

2012

Biology of Reproduction

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“…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. Several UPS proteins have been implicated in the regulation of spermatogenesis, including the E3 ligase Huwe1 (Liu et al 2007). The involvement of the ubiquitin-proteasome system in gonocyte differentiation is not surprising considering the large amount of remodeling taking place during gonocyte development, but further studies are needed to identify the functional enzyme-substrate partners and their respective roles in gonocyte development.…”

Section: Transitional Gonocyte Differentiation In Rodentsmentioning

confidence: 99%

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

Manku¹,

Culty²

2015

Reproduction

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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“…Mass spectrometry and gel filtration analysis indicated that E3 Histone is a monomer of the HECT-containing E3 ligase previously termed LASU1 [40]. A subsequent evaluation of the cell-specific expression of the E3 Histone revealed that its mRNA expression in the testis is highest in rats during postnatal days 10 and 20 and that it decreases with age whereas its protein was found to be highly expressed in the nuclei of spermatogonia through mid-pachytene spermatocytes but was not detected in spermatid subtypes when histones are ubiquitinated and degraded [41]. Therefore, the definitive participation of this E3 ligase in the removal of spermatid histones remains unresolved.…”

Section: Known Testicular E3 Ligases and Their Influence On Spermamentioning

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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Regulated expression of the ubiquitin protein ligase, E3^Histone/LASU1/Mule/ARF‐BP1/HUWE1, during spermatogenesis

Cited by 43 publications

References 45 publications

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

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

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

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

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Regulated expression of the ubiquitin protein ligase, E3Histone/LASU1/Mule/ARF‐BP1/HUWE1, during spermatogenesis

Cited by 43 publications

References 45 publications

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

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

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

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

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Product

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Regulated expression of the ubiquitin protein ligase, E3^Histone/LASU1/Mule/ARF‐BP1/HUWE1, during spermatogenesis