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Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice

ABSTRACT: The product of the Bmal1 locus is an essential component of the circadian clock that plays important roles in various aspects of reproductive biology,and when disrupted results in infertility. In an effort to establish the identity of the tissue specific clock that is responsible for this infertility, we used the steroidogenic factor-1 (Sf1) promoter to drive Cre-mediated recombination and genetically delete Bmal1 within cells of the reproductive axis. We show that Bmal1 within the reproductive axis of females is essential for normal fertility through its role in maintaining implantation, but is not required for normal estrous cycling. At the root of this biology appears to be a defect in the ovaries, including regulation of ovarian lipid biosynthetic or metabolic processes and their roles in maintaining progesterone synthesis. This conclusion is based upon three observations. First, that deletion of Bmal1 within the reproductive axis reducesleads to affected transcripts in steroidogenic pathways for the LH receptor , and lowers progesterone levels. Second, that progesterone supplementation of these conditional mutants rescues implantation. Third, transplantation of wild type ovaries into Bmal1 reproductive axis mutants rescues fertility. Our study demonstrates the significance of ovarian Bmal1 as an overriding influence in experimental models of infertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE48758 | GEO | 2014/10/01

SECONDARY ACCESSION(S): PRJNA211526

REPOSITORIES: GEO

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Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice

Project description:The product of the Bmal1 locus is an essential component of the circadian clock that plays important roles in various aspects of reproductive biology,and when disrupted results in infertility. In an effort to establish the identity of the tissue specific clock that is responsible for this infertility, we used the steroidogenic factor-1 (Sf1) promoter to drive Cre-mediated recombination and genetically delete Bmal1 within cells of the reproductive axis. We show that Bmal1 within the reproductive axis of females is essential for normal fertility through its role in maintaining implantation, but is not required for normal estrous cycling. At the root of this biology appears to be a defect in the ovaries, including regulation of ovarian lipid biosynthetic or metabolic processes and their roles in maintaining progesterone synthesis. This conclusion is based upon three observations. First, that deletion of Bmal1 within the reproductive axis reducesleads to affected transcripts in steroidogenic pathways for the LH receptor , and lowers progesterone levels. Second, that progesterone supplementation of these conditional mutants rescues implantation. Third, transplantation of wild type ovaries into Bmal1 reproductive axis mutants rescues fertility. Our study demonstrates the significance of ovarian Bmal1 as an overriding influence in experimental models of infertility. A time series was performed in time-mated C57Bl/6J mice to identiy oscillating transcripts. During the peak and trough of the majority of transcripts (ZT0 and ZT12) samples from Bmal1fx/fx Sf1Cre mice and control litermates as well and global Bmal1 nulls were also analyzed. The tissue types (ovary, pituitary) are not comparable.

2014-10-01 | E-GEOD-48758 | biostudies-arrayexpress

Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice.

Project description:The product of the Bmal1 locus is an essential component of the circadian clock that plays important roles in various aspects of reproductive biology, and its disruption results in infertility. In an effort to identify the identity of the tissue specific clock that is responsible for this infertility, we used the steroidogenic factor-1 (Sf1) promoter to drive Cre-mediated recombination and genetically delete Bmal1 within cells of the reproductive axis. We show that Bmal1 within the reproductive axis of females is essential for normal fertility through its role in maintaining implantation, but is not required for normal estrous cycling. At the root of this biology appears to be a defect in the regulation of ovarian steroidogenic acute regulator (StAR) and its role in maintaining progesterone synthesis. This conclusion is based upon three observations. First, that deletion of Bmal1 within the reproductive axis leads to lower levels of StAR mRNA, and lower progesterone levels. Second, that progesterone supplementation of these conditional mutants rescues implantation. Third, transplantation of wild type ovaries into Bmal1 reproductive axis mutants results in 100% fertility. Our study suggests that ovarian Bmal1 is an essential peripheral clock governing implantation and fertility in female mice. Ten week old female Bmal1fxfx mice positive or negative for Cre-recombinase driven by the sf-1 promoter, housed in 12 hour light:12 dark, ad lib feeding and drinking conditions were sacrificed at ZT12 on 3.5dpc (3.5 days post copulation). For each array analysis, a pool of 3 RNA samples from 3 individual Bmal1fx/fxCresf-1 ovaries labeled with cy3 were co-hybridized with a pool of 3 RNA samples from Bmal1fx/fx ovaries labeled with cy5, according to Agilent protocols.

2013-02-01 | E-GEOD-38365 | biostudies-arrayexpress

Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice.

Project description:The product of the Bmal1 locus is an essential component of the circadian clock that plays important roles in various aspects of reproductive biology, and its disruption results in infertility. In an effort to identify the identity of the tissue specific clock that is responsible for this infertility, we used the steroidogenic factor-1 (Sf1) promoter to drive Cre-mediated recombination and genetically delete Bmal1 within cells of the reproductive axis. We show that Bmal1 within the reproductive axis of females is essential for normal fertility through its role in maintaining implantation, but is not required for normal estrous cycling. At the root of this biology appears to be a defect in the regulation of ovarian steroidogenic acute regulator (StAR) and its role in maintaining progesterone synthesis. This conclusion is based upon three observations. First, that deletion of Bmal1 within the reproductive axis leads to lower levels of StAR mRNA, and lower progesterone levels. Second, that progesterone supplementation of these conditional mutants rescues implantation. Third, transplantation of wild type ovaries into Bmal1 reproductive axis mutants results in 100% fertility. Our study suggests that ovarian Bmal1 is an essential peripheral clock governing implantation and fertility in female mice.

2013-02-01 | GSE38365 | GEO

Microarray and RNAi Analysis of P450s in Anopheles gambiae Male and Female Steroidogenic Tissues: CYP307A1 is Required for Ecdysteroid Synthesis

Project description:Small-scale microarray profiling of all the genes encoding P450 enzymes of the malaria mosquito Anopheles gambiae in active steroidogenic organs of adults. Ovaries from non blood-fed females were compared to ovaries of blood-fed females at different times after the blood meal: 16 and 22h post-blood-meal, and to male reproductive tracts from males.

2013-09-10 | E-MTAB-1697 | biostudies-arrayexpress

Mus musculus

Project description:Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice

| PRJNA211526 | ENA

Mus musculus

Project description:Targeted disruption of BMAL1 in the peripheral reproductive axis results in infertility in female mice.

| PRJNA167747 | ENA

Polyamine metabolite spermidine rejuvenates the oocyte quality by enhancing mitophagy during female reproductive aging

Project description:Advanced age is a primary risk factor for female infertility due to reduced ovarian reserve and declining oocyte quality. However, as an important contributing factor, the role of metabolic regulation during reproductive aging is poorly understood. Here, we applied untargeted metabolomics to identify spermidine as a critical metabolite in ovaries to protect oocytes against aging. In particular, we found that spermidine level was reduced in aged ovaries and supplementation of spermidine promoted follicle development, oocyte maturation, early embryonic development and female fertility of aged mice. By micro-transcriptomic analysis, we further discovered that recovery of oocyte quality by spermidine was mediated by enhancement of mitophagy activity and mitochondrial function in aged mice, and this action mechanism was conserved in porcine oocytes under oxidative stress. Altogether, our findings demonstrate that spermidine supplementation is a potentially effective strategy to ameliorate oocyte quality and reproductive outcome of women at an advanced age.

2023-11-10 | GSE239551 | GEO

Study of Information Received About Fertility and Infertility in Patients Who Have Finished Treatment for Cancer

Project description:RATIONALE: Learning about the amount of information on fertility and infertility by patients before they received treatment for cancer in a comprehensive cancer center may help doctors plan the best treatment. PURPOSE: This clinical trial is studying the amount of information on fertility and infertility received by patients before treatment of cancer in patients who have finished treatment.

| 2102250 | ecrin-mdr-crc

Transgenic pig over-expressing leptin as a model for female infertility

Project description:Infertility is a growing global health concern affecting millions of couples worldwide. Both overweight and underweight individuals face reproductive issues, resulting in infertility. Due to small size and short life, mice are not necessarily suitable animal models for human infertility. While, pigs having large size, anatomical and physiological similarities with human are considered as more ideal animal model of human disease. Leptin is a well-known adipokine that serves as an endocrine signal between adiposity and fertility. However, the exact mechanisms underlying leptin's effects on reproductive function remain unclear. To shed light on this, our study focused on pigs genetically engineered to overexpress leptin. These leptin-overexpressing pigs exhibited several reproductive abnormalities, including reduced body weight and size, decreased back fat thickness, and displayed late onset of puberty, and irregular estrous behavior characterized by increased inter-estrous interval and more breeding attempts until pregnancy. This reproductive impairment in leptin pigs was followed by hormonal imbalances and altered steroidogenesis. Bulk RNA sequencing of the ovaries revealed neutrophilic infiltration followed by upregulation of inflammation related genes. To gain a deeper understanding of the cellular levels, we employed single-nucleus RNA sequencing (snRNA-seq), and found that leptin overexpression triggered immune response, suppressed follicle development and luteinization, imposing metabolism dysfunction and hormone imbalance in ovary. Further, trends of phenotypical infertility symptoms and endocrine changes in underweight female patients mirrored the alterations observed in our leptin pigs. These findings suggest that leptin-overexpressing pigs could serve as a valuable animal model for studying infertility and investigating potential therapeutic interventions.

2023-07-17 | GSE237153 | GEO

Nano-encapsulated senolytics cocktail ameliorates germ cell senescence in female mice

Project description:Low-quality oocytes directly affect fertilization and embryo developmental ability, and further contributes to infertility in women. Dasatinib and quercetin, as a senolytics, has been explored extensively in various age-related diseases. Here, we report that nano-encapsulated senolytics cocktail (D+Q) efficaciously ameliorates the the quantity and quality of follicles and oocytes in vitro and in vivo. D+Q cocktail supplementation reduces the level of ROS in aged oocytes, decreases the frequency of fragmentation, maintains the spindle integrity, rescues mislocalized cortical granules, rescues mitochondrial membrane potential and alleviates DNA damage and apoptosis in vitro. Nano-encapsulated D+Q cocktail effectively ameliorates the fertility deficits in the cyclophosphamide-induced primary ovarian failure (POF) mice model. Moreover, RNA sequencing analysis shows that D+Q cocktail improves the fecundity of POF mice by increasing development gene expression and reduces the senescence-associated secretory phenotype (SASP) accumulation. Taken together, our data show that the D+Q cocktail helps to improve assisted reproductive technology and reproductive outcomes in POF.

2024-04-23 | GSE264327 | GEO

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