Nampt-mediated spindle sizing secures a post-anaphase increase in spindle speed required for extreme asymmetry

Wei, Zhe; Greaney, Jessica; Loh, Wei‐Guo Nicholas; Homer, Hayden

doi:10.1038/s41467-020-17088-6

Cited by 20 publications

(32 citation statements)

References 53 publications

(120 reference statements)

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“…53,58,59 Furthermore, reducing NAD þ levels through knockdown of the NAD þ synthetic enzyme, NAMPT, in oocytes compromised quality by impairing asymmetric division. 60 Thus, NAD þ has emerged as a pivotal node in the oocyte's aging process and constitutes a promising target for therapeutic approaches aimed at reversing poor quality.…”

Section: Prospects and Challenges For Diagnosing And Improving Poor Omentioning

confidence: 99%

The Role of Oocyte Quality in Explaining “Unexplained” Infertility

Homer

2020

Semin Reprod Med

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Infertility is described as unexplained when pregnancy does not occur despite ovulation, patent Fallopian tubes, and normal semen parameters. Oocyte developmental competence (or quality) is rate-limiting for pregnancy success as oocytes provide virtually all the cellular building blocks including mitochondria required during embryogenesis. However, available tests estimate oocyte numbers (anti-Müllerian hormone, follicle-stimulating hormone and antral follicle count) and ovulation (luteal phase serum progesterone) but not the third, and most pivotal, oocyte-specific parameter, quality. Severe depletion of the follicular reserve manifests as premature ovarian insufficiency and is an obvious cause of anovulation with overt symptoms and clear diagnostic criteria. In contrast, there are no biomarkers of poor oocyte quality other than through in vitro fertilization when readouts of oocyte quality such as preimplantation embryo development can be assessed. The most common cause of poor oocyte quality is natural aging, which is strongly tied to reduced oocyte mitochondrial efficiency and increased oxidative stress. In younger women, quality may also be impaired due to accelerated aging or sporadic genetic mutations which cause severe defects during oocyte and embryo development. Thus, poor oocyte quality often provides an explanation for infertility, but because it cannot be measured using conventional tests, many cases of infertility are often incorrectly labeled “unexplained.” Since female age remains the best predictor of oocyte quality, age over 37 years should be considered an independent diagnostic criterion.

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Section: Prospects and Challenges For Diagnosing And Improving Poor Omentioning

confidence: 99%

The Role of Oocyte Quality in Explaining “Unexplained” Infertility

Homer

2020

Semin Reprod Med

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“…In metaphase, spindle migrates from the center to the cortex, and in anaphase, the spindle continues to migrate outward to induce membrane protrusion required for extremely asymmetric division 25,27,28 . The failure of spindle migration in each phase destroys asymmetric splitting and produces larger PBs 21 . Interestingly, our results showed that DBDPE exposure damaged the migration of anaphase I spindle rather than the migration of metaphase I spindle (Figure 2, Figure S2).…”

Section: Discussionmentioning

confidence: 75%

“…25,27,28 The failure of spindle migration in each phase destroys asymmetric splitting and produces larger PBs. 21 Interestingly, our results showed that DBDPE exposure damaged the migration of anaphase I spindle rather than the migration of metaphase I spindle (Figure 2, Figure S2). Consistent with previous research, 25 DBDPE exposure led to the failure of anaphase I F I G U R E 5 DBDPE exposure inhibited the inactivation of CDK1 in oocytes at the onset of anaphase I.…”

Section: Discussionmentioning

confidence: 79%

“…The increase of cortical F-actin closest to the leading pole of the spindle was caused by the outward migration of the spindle at the onset of anaphase I. 21,25 Thus, the results suggested The entire schedule includes the DBDPE exposure time to mice and the collection of oocytes at different developmental stages. B, The number of oocytes with PBE from mice exposed to different dose of DBDPE (n = 6 mice/group).…”

Section: Dbdpe Exposure Inhibited Cytoplasmic F-actin Polymerization In Oocyte At the Onset Of Anaphase Imentioning

confidence: 95%

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Decabromodiphenyl ethane exposure damaged the asymmetric division of mouse oocytes by inhibiting the inactivation of cyclin‐dependent kinase 1

Shi

Feng

2021

The FASEB Journal

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Decabromodiphenyl ethane (DBDPE) is a new brominated flame retardant and is widely added to flammable materials to prevent fire. Because it has been continuously detected in a variety of organisms and humans, it is important to reveal the biological toxicity of DBDPE. However, the influence of DBDPE for female reproduction is unclear. In this study, we investigated whether and how DBDPE exposure affects oocyte development. Female mice as a model were orally exposed to DBDPE by 0, 0.05, 0.5, 5, 50 μg/kg bw/day for 30 days (0.05 μg/kg bw/day is close to the environmental exposure concentration). We found that exposure of mice to DBDPE did not affect the first polar body extrusion (PBE) of oocytes. Strikingly, however, asymmetric division of oocytes was markedly impaired in 5 and 50 μg/kg bw/day DBDPE exposed group, which resulted in oocytes with larger polar bodies (PBs). Then, we further explored and found that DBDPE exposure inhibited the spindle migration and membrane protrusion in oocytes during anaphase of meiosis I (anaphase I), thereby impairing asymmetric division. Additionally, we found that DBDPE exposure suppressed the inactivation of cyclin‐dependent kinase 1 (Cdk1), resulting in the decrease of cytoplasmic formin2 (FMN2)‐mediated F‐actin polymerization in oocytes at the onset of anaphase I. Simultaneously, DBDPE exposure damaged the structural integrity of the spindle and the perpendicular relationship between spindle and cortex. These together led to the failure of spindle migration and membrane protrusion required for oocytes asymmetric division. Finally, DBDPE exposure injured the development of blastocysts, leading to blastocyst apoptosis.

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“…NAD + in turn regulates oxidative stress in oocytes at least in part via a family of NAD + -dependent deacetylases and deacylases known as sirtuins (SIRT1-7); oocytes from mice over-expressing SIRT2 exhibit delayed aging associated with reduced ROS ( Bertoldo et al, 2020 ), while deletion from oocytes of another sirtuin, SIRT1, results in increased oxidative stress that compromises embryonic development leading to early-onset female infertility ( Iljas et al, 2020 ). Interestingly, the importance of NAD + for oocyte quality extends beyond sirtuin-support roles as it is also critical for enabling oocytes to retain maximum cytoplasmic reserves during meiotic division ( Wei et al, 2020 ). It has also been found that expression of enzymes responsible for producing coenzyme Q10 (CoQ10), a major antioxidant and component of the mitochondrial electron transport chain, is reduced in oocytes from aged mouse and human oocytes ( Ben-Meir et al, 2015 ).…”

Section: Vulnerability Of Oocytes To Oxidative Stress and Dna Damage During Agingmentioning

confidence: 99%

Senataxin: A New Guardian of the Female Germline Important for Delaying Ovarian Aging

Homer

2021

Front. Genet.

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Early decline in ovarian function known as premature ovarian aging (POA) occurs in around 10% of women and is characterized by a markedly reduced ovarian reserve. Premature ovarian insufficiency (POI) affects ~1% of women and refers to the severe end of the POA spectrum in which, accelerated ovarian aging leads to menopause before 40 years of age. Ovarian reserve refers to the total number of follicle-enclosed oocytes within both ovaries. Oocyte DNA integrity is a critical determinant of ovarian reserve since damage to DNA of oocytes within primordial-stage follicles triggers follicular apoptosis leading to accelerated follicle depletion. Despite the high prevalence of POA, very little is known regarding its genetic causation. Another little-investigated aspect of oocyte DNA damage involves low-grade damage that escapes apoptosis at the primordial follicle stage and persists throughout oocyte growth and later follicle development. Senataxin (SETX) is an RNA/DNA helicase involved in repair of oxidative stress-induced DNA damage and is well-known for its roles in preventing neurodegenerative disease. Recent findings uncover an important role for SETX in protecting oocyte DNA integrity against aging-induced increases in oxidative stress. Significantly, this newly identified SETX-mediated regulation of oocyte DNA integrity is critical for preventing POA and early-onset female infertility by preventing premature depletion of the ovarian follicular pool and reducing the burden of low-grade DNA damage both in primordial and fully-grown oocytes.

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Nampt-mediated spindle sizing secures a post-anaphase increase in spindle speed required for extreme asymmetry

Cited by 20 publications

References 53 publications

The Role of Oocyte Quality in Explaining “Unexplained” Infertility

The Role of Oocyte Quality in Explaining “Unexplained” Infertility

Decabromodiphenyl ethane exposure damaged the asymmetric division of mouse oocytes by inhibiting the inactivation of cyclin‐dependent kinase 1

Senataxin: A New Guardian of the Female Germline Important for Delaying Ovarian Aging

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