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Female mice with loss-of-function ITCH display an altered reproductive phenotype.

ABSTRACT: Major progress in deciphering the role of the E3 ligase, ITCH, in animal physiology has come from the generation and identification of Itch loss-of-function mutant mice (itchy). Mutant mice display an autoimmune-like phenotype characterized by chronic dermatitis, which has been attributed to increased levels of ITCH target proteins (e.g. transcription factors JUNB and CJUN) in T cells. Autoimmune disorders also exist in humans with Itch frameshift mutations resulting in loss of functional ITCH protein. Recent phenotypic analysis of male itchy mice revealed reduced sperm production, although cross breeding experiments showed no difference in litter size when male itchy mice were bred to wild type females. However, a reduction in litter sizes did occur when itchy females were bred to wild type males. Based on these results, characterization of female reproductive function in itchy mice was performed. Developmental analysis of fetuses at gestational day 18.5, cytological evaluation of estrous cyclicity, histopathological analysis of ovaries, and protein analysis were used to investigate the itchy reproductive phenotype. Gross skeletal and soft tissue analysis of gestational day 18.5 itchy fetuses indicated no gross developmental deformities. Itchy females had reduced implantation sites, decreased corpora lutea, and increased estrous cycle length due to increased number of days in estrus compared to controls. Alterations in the expression of prototypical ITCH targets in the ovaries were not indicated, suggesting that an alteration in an as yet defined ovary-specific ITCH substrate or interaction with the altered immune system likely accounts for the disruption of female reproduction. This report indicates the importance of the E3 ligase, ITCH, in female reproduction.

SUBMITTER: Stermer AR

PROVIDER: S-EPMC4935413 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Female mice with loss-of-function ITCH display an altered reproductive phenotype.

Stermer Angela R AR Myers Jessica L JL Murphy Caitlin J CJ Di Bona Kristin R KR Matesic Lydia L Richburg John H JH

Experimental biology and medicine (Maywood, N.J.) 20151028 4

Major progress in deciphering the role of the E3 ligase, ITCH, in animal physiology has come from the generation and identification of Itch loss-of-function mutant mice (itchy). Mutant mice display an autoimmune-like phenotype characterized by chronic dermatitis, which has been attributed to increased levels of ITCH target proteins (e.g. transcription factors JUNB and CJUN) in T cells. Autoimmune disorders also exist in humans with Itch frameshift mutations resulting in loss of functional ITCH p ...[more]

PMID: 26515141

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Project description:ContextReproductive function may improve after bariatric surgery, although the mechanisms and time-related changes are unclear.ObjectiveThe objective of the study was to determine whether ovulation frequency/quality as well as associated reproductive parameters improve after Roux en Y gastric bypass surgery.DesignThis was a prospective cohort study that enrolled female subjects from 2005 to 2008 with study visits at baseline and then 1, 3, 6, 12, and up to 24 months after surgery.SettingThe study was conducted at an academic health center.PatientsTwenty-nine obese, reproductive-aged women not using confounding medications participated in the study.Main outcome measuresThe primary outcome was integrated levels of urinary progestin (pregnanediol 3-glururonide) from daily urinary collections at 12 months postoperatively. Secondary outcomes were changes in vaginal bleeding, other biometric, hormonal, ultrasound, dual-energy x-ray absorptiometry measures, and Female Sexual Function Index.ResultsNinety percent of patients with morbid obesity had ovulatory cycles at baseline, and the ovulatory frequency and luteal phase quality (based on integrated pregnanediol 3-glururonide levels) were not modified by bariatric surgery. The follicular phase was shorter postoperatively [6.5 d shorter at 3 months and 7.9-8.9 d shorter at 6-24 months (P < 0.01)]. Biochemical hyperandrogenism improved, largely due to an immediate postoperative increase in serum SHBG levels (P < 0.01), with no change in clinical hyperandrogenism (sebum production, acne, hirsutism). Bone density was preserved, contrasting with a significant loss of lean muscle mass and fat (P < 0.001), reflecting preferential abdominal fat loss (P < 0.001). Female sexual function improved 28% (P = 0.02) by 12 months.ConclusionsOvulation persists despite morbid obesity and the changes from bypass surgery. Reproductive function after surgery is characterized by a shortened follicular phase and improved female sexual function.

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Female mice with loss-of-function ITCH display an altered reproductive phenotype.

Publications

Female mice with loss-of-function ITCH display an altered reproductive phenotype.

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