A single-cell atlas of the aging mouse ovary

Isola, José V. V.; Ocañas, Sarah R.; Hubbart, Chase R.; Ko, Sunghwan; Mondal, Samim Ali; Hense, Jessica D.; Carter, Hannah N. C.; Schneider, Augusto; Kovats, Susan; Alberola-Ila, José; Freeman, Willard M.; Stout, Michael B.

doi:10.1038/s43587-023-00552-5

Cited by 37 publications

(3 citation statements)

References 114 publications

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“…While previous studies of mouse male gonads indicated that both PNMA1 and PNMA4 are expressed at their highest levels in spermatocytes 37 , analysis of mouse female gonads (here and published 25 ) indicated that both genes are primarily expressed in follicular cells. We therefore sought to determine which and to what degree human female gonadal cells express PNMA -family genes.…”

Section: Resultsmentioning

confidence: 53%

“…Pnma1 and Pnma4 are primarily co-expressed (by % positive cells) in granulosa, stroma, and theca cells. Orthogonal analysis of Pnma1 and Pnma4 expression from a published data set 25 corroborated that these genes are expressed in subpopulations of granulosa and stroma cells ( Figures S7A, B ). In granulosa, stroma, and theca, we observed a ∼10-fold decline in Pnma1 -positive cells at post-estropause ( Figure S6 , gray dots).…”

Section: Resultsmentioning

confidence: 55%

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The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

Wood,

Henriques,

Cullen

et al. 2024

Preprint

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The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

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Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 55%

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

Wood,

Henriques,

Cullen

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pnma1 and Pnma4 are primarily co-expressed (by % positive cells) in granulosa, stroma, and theca cells. Orthogonal analysis of Pnma1 and Pnma4 expression from a published data set 25 corroborated that these genes are expressed in subpopulations of granulosa and stroma cells (Figures S9A, B). In granulosa, stroma, and theca, we observed a ~10-fold decline in Pnma1positive cells at post-estropause (Figure S8, gray dots).…”

Section: Male and Female Mice Lacking Pnma1 Or Pnma4 Show Premature L...mentioning

confidence: 55%

The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity

Berchowitz,

Wood,

Henriques

et al. 2024

Preprint

View full text Add to dashboard Cite

The human genome contains 24 gag-like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag-like genes PNMA1 and PNMA4 support reproductive capacity during aging. Analysis of donated human ovaries shows that expression of both genes declines normally with age, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.

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Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling

Weng,

Hong,

Zhang

et al. 2024

Advanced Science

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Sleep deprivation (SD) is observed to adversely affect the reproductive health of women. However, its precise physiological mechanisms remain largely elusive. In this study, using a mouse model of SD, it is demonstrated that SD induces the depletion of ovarian primordial follicles, a phenomenon not attributed to immune‐mediated attacks or sympathetic nervous system activation. Rather, the excessive secretion of stress hormones, namely norepinephrine (NE) and epinephrine (E), by overactive adrenal glands, has emerged as a key mediator. The communication pathway mediated by the KIT ligand (KITL)‐KIT between granulosa cells and oocytes plays a pivotal role in primordial follicle activation. SD heightened the levels of NE/E that stimulates the activation of the KITL‐KIT/PI3K and mTOR signaling cascade in an β2 adrenergic receptor (ADRB2)‐dependent manner, thereby promoting primordial follicle activation and consequent primordial follicle loss in vivo. In vitro experiments further corroborate these observations, revealing that ADRB2 upregulates KITL expression in granulosa cells via the activation of the downstream cAMP/PKA pathway. Together, these results reveal the significant involvement of ADRB2 signaling in the depletion of ovarian primordial follicles under sleep‐deprived conditions. Additionally, ADRB2 antagonists are proposed for the treatment or prevention of excessive activation of primordial follicles induced by SD.

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A single-cell atlas of the aging mouse ovary

Cited by 37 publications

References 114 publications

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

The retrotransposon-derived capsid genesPNMA1andPNMA4maintain reproductive capacity

The Retrotransposon-Derived Capsid Genes PNMA1 and PNMA4 Maintain Reproductive Capacity

Sleep Deprivation Triggers the Excessive Activation of Ovarian Primordial Follicles via β2 Adrenergic Receptor Signaling

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