Aberrant expression of TAR DNA binding protein-43 is associated with spermatogenic disorders in men

Varghese, Divya Saro; Chandran, Uma; Soumya, A.; Pillai, Sathy M.; Jayakrishnan, K; Reddi, Prabhakara P.; Kumar, Pratap

doi:10.1071/rd14090

Cited by 10 publications

(7 citation statements)

References 66 publications

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“…The pattern of spatiotemporal expression of TDP-43 within the seminiferous epithelium (highest expression seen in preleptotene and pachytene spermatocytes) indicates a functional role for the protein in male germ cell differentiation and sperm formation, particularly during meiosis. In support of this, TDP-43 was found to be aberrantly expressed in testicular germ cells and spermatozoa of some infertile men (17). On the basis of the above data, we hypothesized that TDP-43 would be essential for spermatogenesis and male fertility.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 69%

“…Therefore, it is important to identify new factors that contribute to male infertility. Our previous study showed aberrant TDP-43 expression in the spermatozoa of infertile men ( 16 ). In the present study, conditional deletion of TDP-43 in mouse spermatogonia caused failure of meiotic prophase I leading to maturation arrest and severely reduced fertility.…”

Section: Discussionmentioning

confidence: 92%

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Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice

Campbell

Patel

et al. 2021

Journal of Biological Chemistry

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 92%

Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice

Campbell

Patel

et al. 2021

Journal of Biological Chemistry

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“…Indeed, gain-and loss-of-function phenotypes are believed to cause a variety of TDP-43-related proteinopathies (Lee, Lee, & Trojanowski, 2011). Regarding reproduction, TDP-43 is aberrantly expressed in germ cells and sperm obtained from infertile men (Varghese et al, 2016). Thus, TDP-43 is an important protein to study from the point of view of male fertility.…”

mentioning

confidence: 99%

Immunolocalization of TAR DNA‐binding protein of 43 kDa (TDP‐43) in mouse seminiferous epithelium

Osuru

Pramoonjago

Abhyankar

et al. 2017

Molecular Reproduction Devel

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TDP-43 (TAR DNA-binding protein of 43 kDa) is an evolutionarily conserved, ubiquitously expressed, multi-functional DNA/RNA-binding protein with roles in gene transcription, mRNA splicing, stability, transport, micro RNA biogenesis, and suppression of transposons. Aberrant expression of TDP-43 in testis and sperm was recently shown to be associated with male infertility, which highlights the need to understand better the expression of TDP-43 in the testis. We previously cloned TDP-43 from a mouse testis cDNA library, and showed that it functions as a transcriptional repressor, and regulates the precise spatiotemporal expression of the Acrv1 gene, which encodes the acrosomal protein SP-10, during spermatogenesis. Here, we performed immunoblotting and immunohistochemistry of the mouse testis using four separate antibodies recognizing the amino and carboxyl termini of TDP-43. TDP-43 is present in the nuclei of germ cells as well as Sertoli cells. TDP-43 expression begins in type B / intermediate spermatogonia, peaks in preleptotene spermatocytes, and becomes undetectable in leptotene and zygotene spermatocytes. Pachytene spermatocytes and early round spermatids again express TDP-43, but its abundance diminishes later in spermatids (at steps 5 to 8). Interestingly, two of the four antibodies showed TDP-43 expression in spermatids at steps 9–10, which coincides with the initial phase of the histone-to-protamine transition. Immunoreactivity patterns observed in the study suggest that TDP-43 assumes different conformational states at different stages of spermatogenesis. TDP-43 pathology has been extensively studied in the context of neurodegenerative diseases; its role in spermatogenesis warrants further detailed investigation of the involvement of TDP-43 in male infertility.

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“…One report showed low levels of TDP-43-encoding mRNA in testicular germ cells of infertile men. 44 TDP-43 was found to be mislocalized in sperm obtained from infertile patients. 44 Given that a vast majority of male infertility is idiopathic in nature, it is worth estimating the incidence of TDP-43 abnormalities in infertile men.…”

Section: Male Infertilitymentioning

confidence: 95%

Transcription and Splicing Factor TDP-43: Role in Regulation of Gene Expression in Testis

Reddi

2017

Semin Reprod Med

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TDP-43 (AR NA bindingrotein of kD) is a transcription factor and RNA-binding protein with diverse functions. We cloned TDP-43 from the mouse testis in a screen for promoter-binding proteins and showed that it functions as a transcriptional repressor. TDP-43 plays a role in maintaining the precise pattern of spatiotemporal expression of the spermatid-specific gene during spermatogenesis by facilitating RNA polymerase II pausing at the promoter. We also showed that TDP-43 plays a partial role in preventing somatic cell expression of the gene by acting as an insulator-binding protein. Since the discovery of a causative link to several neurodegenerative diseases 10 years ago, TDP-43 has emerged as a protein of major human health relevance. Aberrant posttranslational modifications, nuclear exit, and cytoplasmic aggregate formation contribute to loss of neuronal function in patients. Interestingly, aberrant TDP-43 expression has also been reported in the testis and sperm of infertile men. Finally, our unpublished work shows that TDP-43 is indispensable for sperm formation and male fertility. The potential role of TDP-43 in male germ cells and fertility is discussed in this review.

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Aberrant expression of TAR DNA binding protein-43 is associated with spermatogenic disorders in men

Cited by 10 publications

References 66 publications

Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice

Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice

Immunolocalization of TAR DNA‐binding protein of 43 kDa (TDP‐43) in mouse seminiferous epithelium

Transcription and Splicing Factor TDP-43: Role in Regulation of Gene Expression in Testis

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