Minor Splicing Factors Zrsr1 and Zrsr2 Are Essential for Early Embryo Development and 2-Cell-Like Conversion

Gómez-Redondo, Isabel; Ramos‐Ibeas, Priscila; Pericuesta, Eva; Fernández‐González, Raúl; Laguna‐Barraza, Ricardo; Gutiérrez‐Adán, Alfonso

doi:10.3390/ijms21114115

Cited by 21 publications

(17 citation statements)

References 57 publications

(90 reference statements)

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“…This is consistent with the phenotypes observed in reproductively aging mice with a reduced blastocyst rate and increased apoptotic cells in blastocysts. Recently, evidence has suggested that alternative splicing may be closely related to preimplantation embryonic development, suggesting that splicing may play a key role in regulating early embryonic development (Gómez‐Redondo et al, 2020 ; Xing et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative proteome analysis implicates aberrant RNA splicing in impaired developmental potential of aged mouse oocytes

Ren

Zhou

et al. 2021

Aging Cell

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Aging has many effects on the female reproductive system, among which decreased oocyte quality and impaired embryo developmental potential are the most important factors affecting female fertility. However, the mechanisms underlying oocyte aging are not yet fully understood. Here, we selected normal reproductively aging female mice and constructed a protein expression profile of metaphase II (MII) oocytes from three age groups. A total of 187 differentially expressed (DE) proteins were identified, and bioinformatics analyses showed that these DE proteins were highly enriched in RNA splicing. Next, RNA‐seq was performed on 2‐cell embryos from these three age groups, and splicing analysis showed that a large number of splicing events and genes were discovered at this stage. Differentially spliced genes (DSGs) in the two reproductively aging groups versus the younger group were enriched in biological processes related to DNA damage repair/response. Binding motif analysis suggested that PUF60 might be one of the core splicing factors causing a decline in DNA repair capacity in the subsequent development of oocytes from reproductively aging mice, and changing the splicing pattern of its potential downstream DSG Cdk9 could partially mimic phenotypes in the reproductively aging groups. Taken together, our study suggested that the abnormal expression of splicing regulation proteins in aged MII oocytes would affect the splicing of nascent RNA after zygotic genome activation in 2‐cell embryos, leading to the production of abnormally spliced transcripts of some key genes associated with DNA damage repair/response, thus affecting the developmental potential of aged oocytes.

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Section: Discussionmentioning

confidence: 99%

Integrative proteome analysis implicates aberrant RNA splicing in impaired developmental potential of aged mouse oocytes

Ren

Zhou

et al. 2021

Aging Cell

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“…Primer sequences are provided in Supplementary Table S1 . Expression levels were normalized against that of the endogenous controls H2afz and Actb as described previously [ 43 , 44 ]. PCR conditions were optimized to achieve efficiencies close to 1.…”

Section: Methodsmentioning

confidence: 99%

Postnatal Catch-Up Growth Programs Telomere Dynamics and Glucose Intolerance in Low Birth Weight Mice

Pericuesta

Gutierrez-Arroyo

Sánchez‐Calabuig

et al. 2021

IJMS

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Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.

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“…To calculate ΔΔCT, the highest sample ΔCT value (i.e., the sample showing the lowest target expression) was used as an arbitrary constant to subtract from all other ΔCT sample values. Fold changes in relative gene expression levels of target genes were determined using the formula 2−ΔΔCT [ 67 ]. Gene expression levels were then normalized to those of Actb and H2afz .…”

Section: Methodsmentioning

confidence: 99%

D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome

Pericuesta

Laguna‐Barraza

Ramos‐Ibeas

et al. 2020

IJMS

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Polycystic ovarian syndrome (PCOS) is the main cause of female infertility. It is a multifactorial disorder with varying clinical manifestations including metabolic/endocrine abnormalities, hyperandrogenism, and ovarian cysts, among other conditions. D-Chiro-inositol (DCI) is the main treatment available for PCOS in humans. To address some of the mechanisms of this complex disorder and its treatment, this study examines the effect of DCI on reproduction during the development of different PCOS-associated phenotypes in aged females and two mouse models of PCOS. Aged females (8 months old) were treated or not (control) with DCI for 2 months. PCOS models were generated by treatment with dihydrotestosterone (DHT) on Days 16, 17, and 18 of gestation, or by testosterone propionate (TP) treatment on the first day of life. At two months of age, PCOS mice were treated with DCI for 2 months and their reproductive parameters analyzed. No effects of DCI treatment were produced on body weight or ovary/body weight ratio. However, treatment reduced the number of follicles with an atretic cyst-like appearance and improved embryo development in the PCOS models, and also increased implantation rates in both aged and PCOS mice. DCI modified the expression of genes related to oocyte quality, oxidative stress, and luteal sufficiency in cumulus-oocyte complexes (COCs) obtained from the aged and PCOS models. Further, the phosphorylation of AKT, a main metabolic sensor activated by insulin in the liver, was enhanced only in the DHT group, which was the only PCOS model showing glucose intolerance and AKT dephosphorylation. The effect of DCI in the TP model seemed mediated by its influence on oxidative stress and follicle insufficiency. Our results indicate that DCI works in preclinical models of PCOS and offer insight into its mechanism of action when used to treat this infertility-associated syndrome.

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Minor Splicing Factors Zrsr1 and Zrsr2 Are Essential for Early Embryo Development and 2-Cell-Like Conversion

Cited by 21 publications

References 57 publications

Integrative proteome analysis implicates aberrant RNA splicing in impaired developmental potential of aged mouse oocytes

Integrative proteome analysis implicates aberrant RNA splicing in impaired developmental potential of aged mouse oocytes

Postnatal Catch-Up Growth Programs Telomere Dynamics and Glucose Intolerance in Low Birth Weight Mice

D-Chiro-Inositol Treatment Affects Oocyte and Embryo Quality and Improves Glucose Intolerance in Both Aged Mice and Mouse Models of Polycystic Ovarian Syndrome

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