Distinct Roles for Rac1 in Sertoli Cell Function during Testicular Development and Spermatogenesis

Heinrich, Anna; Potter, Sarah; Li, Guo; Ratner, Nancy; DeFalco, Tony

doi:10.1016/j.celrep.2020.03.077

Cited by 39 publications

(35 citation statements)

References 55 publications

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“…Sertoli cell-formed BTB is polarized, which separates earlier-stage spermatogenic cells basally and later-stage cells apically within the seminiferous epithelium of adult testes 11 . Recently, it was revealed that Rac1 deficiency in Sertoli cells was correlated with defects in cell polarity, which was manifested by the mis-localization of polarity proteins and the disruption of the BTB 20 . While the mechanism remained elusive.…”

Section: Resultsmentioning

confidence: 99%

“…Within the Rho GTPases family, Rac1 has been most extensively characterized 18 . Recently, Rac1 has been demonstrated to be required for Sertoli cell polarity and BTB integrity during later stages of spermatogenesis 20 . Although Rac1 is dispensable for the establishment and maintenance of undifferentiated spermatogonia and for fetal testis differentiation, Sertoli Rac1 in adult testis is required for later stages of spermatogenesis and spermiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been proposed that Rac1 acts as a downstream of mechanistic target of rapamycin kinase complex 1 (mTORC1) to establish the cytoarchitecture of Sertoli cells 19 . Although the function of Sertoli Rac1 is dispensable for fetal testicular differentiation and the maintenance of undifferentiated spermatogonia, in the adult testis, Rac1 deficiency results in severe defects in cell polarity and disruption of the BTB 20 . Sertoli cell polarity is mainly regulated by proteins such as PAR6 and YWHAZ (also known as 14-3-3ζ), and confers cell adhesion at the interface of adjacent Sertoli cells on BTB 21 .…”

Section: Introductionmentioning

confidence: 99%

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Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells

Hu¹,

Zhu²,

Song³

et al. 2021

Theranostics

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Rationale: Radiotherapy has become a mainstay for tumor management, and more than 50% of patients with thoracic tumor need to be treated with radiotherapy. However, the potential adverse effects of thoracic radiotherapy on the reproductive system remain elusive. Methods: Western blot analysis, immunofluorescence assay and transmission electron microscopy (TEM) analysis were performed to investigate the integrity of blood-testis barrier (BTB) in male mice after hypofractionated irradiation (IR) on the right thorax. RNA sequencing, co-immunoprecipitation (IP), Duolink PLA and inhibitor experiments were carried out to demonstrate the molecular mechanisms of the BTB dynamics changes and the subsequent reproductive effect. Results: It was found that the hypofractionated IR on right thorax evoked ultrastructural destruction in distant testes, and thus caused radiation-induced abscopal reproductive effect (RIARE) in male mice. Mechanistically, thoracic IR induced significant nuclear translocation of Rac Family Small GTPase 1 (Rac1) in abscopal Sertoli cells, which closely correlated with the activation of TNF-α/p38 mitogen activated protein kinase (MAPK) pathway. Of note, YWHAZ, a critical polarity protein, was found to be co-localized with Rac1 in Sertoli cells, and this interaction was indispensable for thoracic IR-induced Rac1 nuclear translocation and subsequent degradation of BTB-associated proteins. Conclusions: Our findings imply for the first time that YWHAZ-mediated Rac1 nuclear translocation plays central roles in RIARE, and TNF-α/p38 MAPK/Rac1 axis can be employed as a therapeutic target against RIARE for young male patients receiving hypofractionated radiotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells

Hu¹,

Zhu²,

Song³

et al. 2021

Theranostics

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show abstract

“…To analyze the role of Cdc42 in Sertoli cells in vivo, Cdc42 conditional knockout mice were generated using Dhh-Cre (referred to as "cKO" hereafter), which we recently confirmed is highly specific and effective for targeting Sertoli cells starting as early as E12.5 (Heinrich et al, 2020). Previously published cell-type-specific and single-cell transcriptome studies indicated that Cdc42 is highly expressed in multiple testicular cell types, including Sertoli cells, starting at the earliest stages of testicular differentiation until adulthood (Figures S1A-S1D) (Green et al, 2018;Jameson et al, 2012;Stevant et al, 2018).…”

Section: Cdc42 In Sertoli Cells Is Essential For Adult Steady-state Spermatogenesismentioning

confidence: 99%

Cdc42activity in Sertoli cells is essential for maintenance of spermatogenesis

Bhandary

Heinrich

Potter

et al. 2021

Preprint

Self Cite

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SUMMARYSertoli cells are highly polarized testicular supporting cells that simultaneously nurture progressively maturing germ cells. Proper localization of polarity protein complexes within Sertoli cells, including those responsible for blood-testis barrier formation, are vital for successful spermatogenesis. However, the mechanisms and developmental timing that underlie the establishment of polarity are poorly understood. To investigate this aspect of testicular function, we conditionally deleted Cdc42, encoding a Rho GTPase involved in regulating cell polarity, specifically in Sertoli cells. Cdc42 deletion disrupted adult Sertoli cell maturation and localization of polarity proteins, but did not affect fetal and early postnatal testicular development, nor the onset of the first wave of spermatogenesis. By early adulthood, however, conditional knockout males exhibited a loss of spermatogenic cells, resulting in a complete lack of sperm. These findings demonstrate that Cdc42 plays an essential role in establishing adult Sertoli cell polarity and, thus, maintaining steady-state spermatogenesis and healthy sperm production.

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“…Here, we report a lower number of Sertoli cells in cKO seminiferous tubules. Although Sertoli cells regulate the number of germ cells and Leydig cells during testicular development (Rebourcet et al, 2017;Heinrich et al, 2020), a postnatal effect on the number of PMCs has not been reported. Given that the proliferation of PMCs takes place earlier than that of Sertoli cells when induced by neonatal hemicastration or administration of follicle stimulating hormone (Nurmio et al, 2012) and that Sertoli cell ablation in neonatal testis with benzalkonium chloride does not affect the number of PMCs in vitro (Yokonishi et al, 2020), it is possible that the number of Sertoli cells is affected by testicular smooth muscle cells in postnatal testicular development.…”

Section: Testicular Smooth Muscle Cells Might Affect Numbers Of Sertomentioning

confidence: 99%

Development and function of smooth muscle cells is modulated by Hic1 in mouse testis

et al. 2020

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In mammalian testis, contractile peritubular myoid cells (PMCs) regulate the transport of sperm and luminal fluid, while secreting growth factors and extracellular matrix proteins to support the spermatogonial stem cell niche. However, little is known about the role of testicular smooth muscle cells during postnatal testicular development. Here we report age-dependent expression of hypermethylated in cancer 1 (Hic1; also known as ZBTB29) in testicular smooth muscle cells, including PMCs and vascular smooth muscle cells, in the mouse. Postnatal deletion of Hic1 in smooth muscle cells led to their increased proliferation and resulted in dilatation of seminiferous tubules, with increased numbers of PMCs. These seminiferous tubules contained fewer Sertoli cells and more spermatogonia, and fibronectin was not detected in their basement membrane. The expression levels of genes encoding smooth muscle contractile proteins, Acta2 and Cnn1, were downregulated in the smooth muscle cells lacking Hic1, and the seminiferous tubules appeared to have reduced contractility. These data imply a role for Hic1 in determining the size of seminiferous tubules by regulating postnatal smooth muscle cell proliferation, subsequently affecting spermatogenesis in adulthood.

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Distinct Roles for Rac1 in Sertoli Cell Function during Testicular Development and Spermatogenesis

Cited by 39 publications

References 55 publications

Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells

Radiation-induced abscopal reproductive effect is driven by TNF-α/p38 MAPK/Rac1 axis in Sertoli cells

Cdc42activity in Sertoli cells is essential for maintenance of spermatogenesis

Development and function of smooth muscle cells is modulated by Hic1 in mouse testis

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