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

Campbell, Kaitlyn M.; Xu, Yiding; Patel, Chintan; Rayl, Jeremy M.; Zomer, Helena Debiazi; Osuru, Hari Prasad; Pratt, Michael F.; Pramoonjago, Patcharin; Timken, Madeline; Miller, Lyndzi M.; Ralph, Abigail; Storey, Kathryn M.; Peng, Yiheng; Drnevich, Jenny; Lagier‐Tourenne, Clotilde; Wong, Philip C.; Qiao, Huanyu; Reddi, Prabhakara P.

doi:10.1016/j.jbc.2021.101231

Cited by 10 publications

(19 citation statements)

References 76 publications

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“…(1) Mutation of the TDP‐43 binding motifs within the Acrv1 promoter led to premature expression of a reporter in spermatocytes 39 . (2) Loss of TDP‐43 by gene knockout in mice led to the premature expression of the endogenous Acrv1 gene in spermatocytes 51 . Taken together, our data support the hypothesis that TDP‐43 is required for maintaining the spatiotemporal gene expression of the Acrv1 gene in the seminiferous epithelium.…”

Section: Introductionsupporting

confidence: 70%

“…Testing of the above hypothesis in vivo was possible when we generated the Tardbp (TDP-43) conditional knockout mice using the Stra8-iCre deleter strain. 51 Loss of TDP-43 in spermatogonia caused differentiation arrest during prophase I of meiosis. But, because of the delay in Cre-mediated excision of the floxed gene in a fraction of the seminiferous tubules as reported previously in the case of Stra8-iCre, 52 spermatocytes did undergo meiosis and round spermatid formation occurred.…”

Section: Tdp-43 Is Required To Maintain Spatiotemporal Expression Of ...mentioning

confidence: 99%

“…This was ideal for addressing the status of expression of the endogenous Acrv1 in spermatocytes which lacked TDP‐43. Immunohistochemistry indeed showed that in TDP‐43 cKO mice, the Acrv1 gene product SP‐10 was prematurely expressed in spermatocytes whereas control mice expressed SP‐10 only in round spermatids 51 . Thus, two lines of evidence pointed to the role of TDP‐43 in preventing premature expression of Acrv1 in spermatocytes.…”

Section: Introductionmentioning

confidence: 96%

“…Testing of the above hypothesis in vivo was possible when we generated the Tardbp (TDP‐43) conditional knockout mice using the Stra8‐iCre deleter strain 51 . Loss of TDP‐43 in spermatogonia caused differentiation arrest during prophase I of meiosis.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

Reddi

2023

Andrology

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Precise spatiotemporal expression of cohorts of differentiation markers unique to spermatogonia, spermatocytes, and round spermatids punctuates spermatogenesis and ensures its completion. For example, genes coding for the synaptonemal complex or the acrosome or flagellum are expressed sequentially in a developmental stageand germ cell-specific manner. But the transcriptional mechanisms governing the spatiotemporal order of gene expression within the seminiferous epithelium are poorly understood. Using the round spermatid-specific Acrv1 gene, which codes for the acrosomal protein SP-10 as a model, we learned that (1) the proximal promoter itself contains all the necessary cis-regulatory sequences, (2) an insulator prevents somatic cell expression of the testis-specific gene, (3) RNA II polymerase is loaded on the Acrv1 promoter but paused in spermatocytes, thus ensuring precise transcriptional elongation in round spermatids, and that (4) a transcriptional repressor binding protein of 43 kilodaltons (TDP-43) plays a role in maintaining the paused state in spermatocytes. Although the Acrv1 enhancer element has been narrowed down to 50 bp and its binding to a 47 kDa testis-abundant nuclear protein shown, the identity of the putative transcription factor responsible for activation of round spermatid-specific transcription remains elusive. Human male infertility is idiopathic with limited treatment options. Understanding transcriptional regulation of spermatogenesis has the potential to lead to future therapies for male infertility.

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Section: Introductionsupporting

confidence: 70%

Section: Tdp-43 Is Required To Maintain Spatiotemporal Expression Of ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

Reddi

2023

Andrology

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“…[20] In line with this, a loss of function of TDP-43 in male mouse models resulted in a meiotic arrest in the process of spermatogenesis. [21] The homodimerization and nuclear localization of TDP-43 are assigned to AA 4-77. However, the minimal essential domain of TDP-43 that exhibits the homodimerization capability is not known.…”

Section: Introductionmentioning

confidence: 99%

An N-terminal peptide of Tar DNA binding Protein 43 lacking nuclear localization signal translocates to the nucleus of GC-1 spermatogonial cells

Varghese

Vysakh

Kumar

2023

JRHM

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Objectives: TAR DNA-binding protein of 43 kDa (TDP-43) is an RNA/DNA binding protein expressed in the brain and the testis. Mutations in TDP-43 lead to mislocalization and cytoplasmic aggregation of this protein causing neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 has also been implicated in maintaining spermatogenesis. While homodimerization of TDP-43 is critical for its physiological functions, higher-order aggregation of this protein impairs its functions. This study was aimed to map the critical amino acids of the N-terminus of this protein in mediating its homodimerization. Materials and Methods: We generated deletion constructs of Tdp-43 containing NRRM1 domain alone (TDP-43∆3-183) and N-terminal peptide of TDP-43 which lacks the nuclear localization signal (NLS) (TDP-43∆1-50) with fluorescent reporters having non-overlapping emission properties. These constructs were co-transfected into a mouse spermatogonial cell line to examine their dimerization and nuclear translocation capabilities in vitro. Results: We found that TDP-43∆3-183 alone was not capable of homodimerization. On the other hand, TDP-43∆1-50 when co-transfected into GC1-spg cells along with full length TDP-43 translocated to the nucleus oligomerized with the latter and translocated to the nucleus, indicating the importance of amino acids 1-50 of TDP-43 in dimerization. Conclusion: The N-terminal segment of TDP-43 spanning amino acids 1-50 is responsible for dimerization, while that spanning amino acids 51-183 directs it to the nucleus.The physiological and pathological implications of this finding need to be examined.

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PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac⁴C Formation in Mammalian Cells

Jiang,

Wu,

Deng

et al. 2024

Advanced Science

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Massive numbers of modified bases in mRNAs sculpt the epitranscriptome and play vital roles in RNA metabolism. The only known acetylated RNA modification, N‐4‐acetylcytidine (ac4C), is highly conserved across cell types and among species. Although the GCN5‐related acetyltransferase 10 (NAT10) functions as an ac4C writer, the mechanism underlying the acetylation process is largely unknown. In this study, the NAT10/PCBP/TDP43 complex mediated mRNA ac4C formation in mammalian cells is identified. RNA‐binding proteins (RBPs) are identified, affiliated with two different families, poly(rC)‐binding protein 1/2 (PCBP1/2) and TAR DNA binding protein 43 (TDP43), as NAT10 adaptors for mRNA tethering and substrate selection. Knockdown of the adaptors resulted in decreased mRNA acetylation abundance in HEK293T cells and ablated cytidine‐rich ac4C motifs. The adaptors also affect the ac4C sites by recruiting NAT10 to their binding sequences. The presence of the NAT10/PCBP/TDP43 complex in mouse testes highlights its potential physiological functions in vivo. These findings reveal the composition of the mRNA ac4C writer complex in mammalian cells and expand the knowledge of mRNA acetylation and ac4C site preferences.

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

Cited by 10 publications

References 76 publications

Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

An N-terminal peptide of Tar DNA binding Protein 43 lacking nuclear localization signal translocates to the nucleus of GC-1 spermatogonial cells

PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac⁴C Formation in Mammalian Cells

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

Cited by 10 publications

References 76 publications

Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

Transcriptional regulation of spatiotemporal gene expression within the seminiferous epithelium: Mouse Acrv1 gene as a model

An N-terminal peptide of Tar DNA binding Protein 43 lacking nuclear localization signal translocates to the nucleus of GC-1 spermatogonial cells

PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac4C Formation in Mammalian Cells

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PCBP1/2 and TDP43 Function as NAT10 Adaptors to Mediate mRNA ac⁴C Formation in Mammalian Cells