Loss of function of Ywhah in mice induces deafness and cochlear outer hair cell’s degeneration

Buret, L; Delprat, Benjamin; Delettre, Cécile

doi:10.1038/cddis.2016.88

Cited by 4 publications

(3 citation statements)

References 13 publications

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“…This indicates that YWHAH protein is not essential for female reproduction and early embryonic development and, given the importance of YWHA in many cellular events, other isoforms of YWHA might substitute. Normal morphology and presumably normal fertility in female YWHAH knockout mice have also been recently reported by other investigators who found that absence of YWHAH protein leads to deafness and hair cell degeneration [66].…”

Section: Discussionsupporting

confidence: 66%

YWHA (14-3-3) protein isoforms and their interactions with CDC25B phosphatase in mouse oogenesis and oocyte maturation

Eisa

Detwiler

et al. 2019

BMC Dev Biol

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BackgroundImmature mammalian oocytes are held arrested at prophase I of meiosis by an inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1). Release from this meiotic arrest and germinal vesicle breakdown is dependent on dephosphorylation of CDK1 by the protein, cell cycle division 25B (CDC25B). Evidence suggests that phosphorylated CDC25B is bound to YWHA (14-3-3) proteins in the cytoplasm of immature oocytes and is thus maintained in an inactive form. The importance of YWHA in meiosis demands additional studies.ResultsMessenger RNA for multiple isoforms of the YWHA protein family was detected in mouse oocytes and eggs. All seven mammalian YWHA isoforms previously reported to be expressed in mouse oocytes, were found to interact with CDC25B as evidenced by in situ proximity ligation assays. Interaction of YWHAH with CDC25B was indicated by Förster Resonance Energy Transfer (FRET) microscopy. Intracytoplasmic microinjection of oocytes with R18, a known, synthetic, non-isoform-specific, YWHA-blocking peptide promoted germinal vesicle breakdown. This suggests that inhibiting the interactions between YWHA proteins and their binding partners releases the oocyte from meiotic arrest. Microinjection of isoform-specific, translation-blocking morpholino oligonucleotides to knockdown or downregulate YWHA protein synthesis in oocytes suggested a role for a specific YWHA isoform in maintaining the meiotic arrest. More definitively however, and in contrast to the knockdown experiments, oocyte-specific and global deletion of two isoforms of YWHA, YWHAH (14-3-3 eta) or YWHAE (14-3-3 epsilon) indicated that the complete absence of either or both isoforms does not alter oocyte development and release from the meiotic prophase I arrest.ConclusionsMultiple isoforms of the YWHA protein are expressed in mouse oocytes and eggs and interact with the cell cycle protein CDC25B, but YWHAH and YWHAE isoforms are not essential for normal mouse oocyte maturation, fertilization and early embryonic development.

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Section: Discussionsupporting

confidence: 66%

YWHA (14-3-3) protein isoforms and their interactions with CDC25B phosphatase in mouse oogenesis and oocyte maturation

Eisa

Detwiler

et al. 2019

BMC Dev Biol

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“…A statement in one report on 14‐3‐3ζ 22 stated that males and females lacking this isoform are infertile,however, there was no supporting data or examination and discussion of the infertility phenotype. The absence of 14‐3‐3η in knockout mice results in deafness and degeneration of cochlear cells 23 . There was also a mention in this report that 14‐3‐3η knockout males were infertile but there was no supporting data or discussion.…”

Section: Discussionmentioning

confidence: 77%

The protein YWHAE (14‐3‐3 epsilon) in spermatozoa is essential for male fertility

et al. 2020

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Background Spermatogenesis is a complex biological process highlighted by synthesis and activation of proteins that regulate meiosis and cellular differentiation occur during spermatogenesis. 14‐3‐3 proteins are adaptor proteins that play critical roles in kinase signaling, especially for regulation of cell cycle and apoptosis in eukaryotic cells. There are seven isoforms of the 14‐3‐3 family proteins encoded by seven genes (β, ε, γ, η, θ/τ, ζ and σ). 14‐3‐3 isoforms have been shown to have many interacting partners in several tissues including testis. Objective While it is known that 14‐3‐3 proteins are expressed in the functions of testis and spermatozoon, the role for each of the seven isoforms is not known. In this study, we investigated the roles of 14‐3‐3η and 14‐3‐3ε isoforms in spermatogenesis. Materials and methods To study the in vivo function of 14‐3‐3η and 14‐3‐3ε in spermatogenesis, we generated testis‐specific and global knockout mice for each of 14‐3‐3η and 14‐3‐3ε isoforms (CKO and GKO, respectively). Computer‐assisted semen analysis was used to assess sperm motility, while immunohistochemical studies were conducted to check spermatogenesis. Results Although both 14‐3‐3η and 14‐3‐3ε isoforms were present in mouse testis, only the expression of 14‐3‐3ε, but not 14‐3‐3η, was detected in spermatozoa. Mice lacking 14‐3‐3η were normal and fertile while 14‐3‐3ε CKO and GKO males showed infertility. Low sperm count with higher abnormal spermatozoa was seen in 14‐3‐3ε CKO mice. The motility of 14‐3‐3ε knockout spermatozoa was lower than that of the control. A reduction in the phosphorylation of both glycogen synthase kinase 3 and PP1γ2 was also seen in spermatozoa from 14‐3‐3ε CKO mice, suggesting a specific role of 14‐3‐3ε in spermatogenesis, sperm motility, and fertility. Discussion and conclusion This is the first demonstration that of the seven 14‐3‐3 isoforms, 14‐3‐3ε is essential for normal sperm function and male fertility.

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“…Indeed, several genes involved in antiapoptotic signalling were found downregulated (e.g. TUBA1B, NAIP, YWHAG, YWHAQ, BCL2, BCL2L1, GLUD1 and ACTG1; Figure 4C) [62][63][64][65][66][67][68] . To confirm the alteration of these pathways on a larger scale, we performed a DGE analysis between BD and CT samples on a publicly available bulk RNA sequencing dataset, including over 200 samples from the Cg and the amygdala, published by Zandi et al 15 .…”

Section: Microglia In Bd Are Characterized By Reduced Proinflammatory...mentioning

confidence: 99%

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Amossé,

Tournier,

Badina

et al. 2023

Preprint

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Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis ofpostmortemcingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated toADCY2andNCAN,two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

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Loss of function of Ywhah in mice induces deafness and cochlear outer hair cell’s degeneration

Cited by 4 publications

References 13 publications

YWHA (14-3-3) protein isoforms and their interactions with CDC25B phosphatase in mouse oogenesis and oocyte maturation

YWHA (14-3-3) protein isoforms and their interactions with CDC25B phosphatase in mouse oogenesis and oocyte maturation

The protein YWHAE (14‐3‐3 epsilon) in spermatozoa is essential for male fertility

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

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