CART (for 'cocaine- and amphetamine-regulated transcript') is a brain-located peptide, is a satiety factor and is closely associated with the actions of 2 important regulators of food intake, leptin (164160), and neuropeptide Y (162640). Food-deprived animals showed a pronounced decrease in expression of CART mRNA in the arcuate nucleus. In animal models of obesity with disrupted leptin signaling, CART mRNA was almost absent from the arcuate nucleus. Peripheral administration of leptin to obese mice stimulated CART mRNA expression. When injected intracerebroventricularly into rats, recombinant CART peptide inhibited both normal and starvation-induced feeding, and completely blocked the feeding response induced by neuropeptide Y. An antiserum against CART increased feeding in normal rats, indicating that CART may be an endogenous inhibitor of food intake in normal animals. Cocaine- and amphetamine-regulated transcript (CART) is an anorexigenic peptide widely expressed in the central and peripheral, including the enteric, nervous systems. CART is also expressed in pituitary endocrine cells, adrenomedullary cells, islet somatostatin cells, and in rat antral gastrin cells.
NCBI Summary:
This gene encodes a preproprotein that is proteolytically processed to generate multiple biologically active peptides. These peptides play a role in appetite, energy balance, maintenance of body weight, reward and addiction, and the stress response. Expression of a similar gene transcript in rodents is upregulated following administration of cocaine and amphetamine. Mutations in this gene are associated with susceptibility to obesity in humans. [provided by RefSeq, Feb 2016]
General function
Ligand
Comment
Cellular localization
Secreted
Comment
Ovarian function
Steroid metabolism
Comment
Study on the relationship between expression patterns of cocaine-and amphetamine regulated transcript and hormones secretion in porcine ovarian follicles. Li P et al. (2018) Cocaine-and amphetamine regulated transcript (CART) is an endogenous neuropeptide, which is widespread in animals, plays a key role in regulation of follicular atresia in cattle and sheep. Among animal ovaries, CART mRNA was firstly found in the cattle ovaries. CART was localized in the antral follicles oocytes, granulosa and cumulus cells by immunohistochemistry and in situ hybridization. Further research found that secretion of E2was inhibited in granulosa cells with a certain dose of CART, the effect depends on the stage of cell differentiation, suggesting that CART could play a crucial role in regulating follicle atresia. The objective of this study was to characterize the CART expression model and hormones secretion in vivo and vitro in pig follicle granulosa cells, preliminarily studied whether CART have an effect on granulosa cells proliferation and hormones secretion in multiparous animals such as pigs. The expression levels of CART mRNA in granulosa cells of different follicles were analyzed using qRT-PCR technology. Immunohistochemistry technology was used to localize CART peptide. Granulosa cells were cultured in medium supplemented with different concentrations of CART and FSH for 168 h using Long-term culture system, and observed using a microscope. The concentration of Estradiol (E2) and progesterone (P) in follicular fluids of different test groups were detected by enzyme linked immunosorbent assay (ELISA). Results showed that expression level of CART mRNA was highest in medium follicles, and significantly higher than that in large and small follicles (P < 0.05). Immunohistochemical results showed that CART were expressed both in granulosa cells and theca cells of large follicles, while CART were detected only in theca cells of medium and small follicles. After the granulosa cells were cultured for 168 h, and found that concentrations of E2increase with concentrations of follicle-stimulating hormone (FSH) increase when the CART concentration was 0 μM. And the concentration of FSH reached 25 ng/mL, the concentration of E2is greatest. It shows that the production of E2needs induction of FSH in granulosa cells of pig ovarian follicles. With the increasing of CART concentrations (0.01, 0.1, 1 μM), E2concentration has a declining trend, when the FSH concentrations were 25 and 50 ng/mL in the medium, respectively. These results suggested that CART plays a role to inhibit granulosa cells proliferation and E2production, which induced by FSH in porcine ovarian follicular granulosa cells in vitro, but the inhibition effect is not significant. So we hypothesis CART maybe not a main local negative regulatory factor during porcine follicular development, which is different from the single fetal animals.//////////////////
Study on the relationship between expression patterns of cocaine-and amphetamine regulated transcript and hormones secretion in porcine ovarian follicles. Li P et al. (2018) Cocaine-and amphetamine regulated transcript (CART) is an endogenous neuropeptide, which is widespread in animals, plays a key role in regulation of follicular atresia in cattle and sheep. Among animal ovaries, CART mRNA was firstly found in the cattle ovaries. CART was localized in the antral follicles oocytes, granulosa and cumulus cells by immunohistochemistry and in situ hybridization. Further research found that secretion of E2was inhibited in granulosa cells with a certain dose of CART, the effect depends on the stage of cell differentiation, suggesting that CART could play a crucial role in regulating follicle atresia. The objective of this study was to characterize the CART expression model and hormones secretion in vivo and vitro in pig follicle granulosa cells, preliminarily studied whether CART have an effect on granulosa cells proliferation and hormones secretion in multiparous animals such as pigs. The expression levels of CART mRNA in granulosa cells of different follicles were analyzed using qRT-PCR technology. Immunohistochemistry technology was used to localize CART peptide. Granulosa cells were cultured in medium supplemented with different concentrations of CART and FSH for 168 h using Long-term culture system, and observed using a microscope. The concentration of Estradiol (E2) and progesterone (P) in follicular fluids of different test groups were detected by enzyme linked immunosorbent assay (ELISA). Results showed that expression level of CART mRNA was highest in medium follicles, and significantly higher than that in large and small follicles (P < 0.05). Immunohistochemical results showed that CART were expressed both in granulosa cells and theca cells of large follicles, while CART were detected only in theca cells of medium and small follicles. After the granulosa cells were cultured for 168 h, and found that concentrations of E2increase with concentrations of follicle-stimulating hormone (FSH) increase when the CART concentration was 0 μM. And the concentration of FSH reached 25 ng/mL, the concentration of E2is greatest. It shows that the production of E2needs induction of FSH in granulosa cells of pig ovarian follicles. With the increasing of CART concentrations (0.01, 0.1, 1 μM), E2concentration has a declining trend, when the FSH concentrations were 25 and 50 ng/mL in the medium, respectively. These results suggested that CART plays a role to inhibit granulosa cells proliferation and E2production, which induced by FSH in porcine ovarian follicular granulosa cells in vitro, but the inhibition effect is not significant. So we hypothesis CART maybe not a main local negative regulatory factor during porcine follicular development, which is different from the single fetal animals.//////////////////
Intrafollicular expression and potential regulatory role of cocaine- and amphetamine-regulated transcript in the ovine ovary. Huang Y et al. (2015) Follicular growth is regulated by a complex interaction of pituitary gonadotropins with local regulatory molecules. Previous studies demonstrated an important role for cocaine- and amphetamine-regulated transcript (CART) in regulation of granulosa cell estradiol production associated with dominant follicle selection in cattle. However, intraovarian expression and actions of CART in other species, including sheep, are not known. The objective of this study was to investigate the expression of CART in sheep follicles and determine the effects of CART on indices of ovine granulosa cell function linked to follicular development. Results demonstrated the expression of CART messenger RNA and prominent intraovarian localization of CART peptide in granulosa cells of sheep follicles. Granulosa cell CART messenger RNA was lower, but follicular fluid estradiol concentrations were higher in large (>5 mm) follicles vs smaller 3- to 5-mm follicles harvested from sheep ovaries of abattoir origin. CART treatment inhibited follicle stimulating hormone-induced estradiol production by cultured ovine granulosal cells and also blocked the follicle stimulating hormone-induced increase in granulosa cell numbers. Results demonstrate expression of CART in sheep follicular tissues and suggest potential biological actions of CART, which are inhibitory to ovine follicular growth and development.//////////////////
Lower Cocaine- and Amphetamine-Regulated Transcript Levels Pose a Risk for Developing PCOS. Yilmaz O 2014 et al.
Cocaine- and amphetamine-regulated transcript (CART) is an anorectic neuropeptide abundantly expressed in the central, peripheral, and enteric nervous systems, as well as in several different endocrine cell types. Besides regulating food intake and endocrine function, it is also proposed to modulate ovarian function during follicular waves in cattle and has potent inhibitory effects on follicular development. Polycystic ovary syndrome (PCOS), presenting itself with multiple follicular ovarian cysts, is the most common endocrinological disorder among women of reproductive age. Here we aimed to investigate the association of this peptide with PCOS. Our research was designed as a case-control study, in which a total of 148 subjects (73 with PCOS and 75 age- and BMI-matched Controls) were consecutively recruited. Fasting blood glucose (FBG), insulin, high-sensitivity C-reactive protein, lipids, follicle stimulating hormone, luteinizing hormone, estradiol, CART, and free testosterone levels were measured in all participants. Homeostasis model assessment of insulin resistance (HOMA-IR) and body mass index (BMI) were calculated. CART levels were found to be significantly lower in patients with PCOS (PCOS: 90.775.98?pg/ml, Controls: 93.248.17?pg/ml, p=0.038). Pearson's correlation analysis showed that CART was significantly and negatively correlated with BMI and waist circumference in both (PCOS and control) groups. In Controls only, CART was positively correlated with insulin and HOMA-IR, and negatively correlated with FBG. Logistic regression analysis results are suggestive of a possible protective effect of CART against PCOS (OR: 0.94, 95% CI=0.888-0.997, p=0.038).
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Regulation of Granulosa Cell Cocaine and Amphetamine Regulated Transcript (CART) Binding and Effect of CART Signaling Inhibitor on Granulosa Cell Estradiol Production During Dominant Follicle Selection in Cattle. Folger JK 2013 et al.
We previously established a potential role for CARTPT in dominant follicle selection in cattle. CARTPT expression is elevated in subordinate versus dominant follicles and treatment with the mature form of the CARTPT peptide (CART) decreases FSH-stimulated granulosa cell estradiol production in vitro and follicular fluid estradiol and granulosa cell CYP19A1 mRNA in vivo. However, mechanisms that regulate granulosa cell CART responsiveness are not understood. In this study, we investigated hormonal regulation of granulosa cell CART binding sites in vitro and temporal regulation of granulosa cell CART binding sites in bovine follicles collected at specific stages of a follicular wave. We also determined the effect of inhibition of CART receptor signaling in vivo on estradiol production in future subordinate follicles. Granulosa cell CART binding in vitro was increased by FSH and this induction was blocked by estrogen receptor antagonist treatment. In follicles collected in vivo at specific stages of a follicular wave, granulosa cell CART binding in the F2 (second largest), future subordinate follicle increased during dominant follicle selection. Injection into the F2 follicle (at onset of deviation) of an inhibitor of the o/i subclass of G proteins (previously shown to block CART actions in vitro) resulted in increased follicular fluid estradiol concentrations in vivo. Collectively, results demonstrate hormonal regulation of granulosa cell CART binding in vitro and temporal regulation of CART binding in subordinate follicles during dominant follicle selection. Results also suggest that CART signaling may help suppress estradiol producing capacity of the F2 (subordinate) follicle during this time period.
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Supporting a Role for Cocaine- and Amphetamine-Regulated Transcript (CARTPT) in Control of Granulosa Cell Estradiol Production Associated with Dominant Follicle Selection in Cattle. Lv L et al. We previously demonstrated a negative association of granulosa cell cocaine-and amphetamine-regulated transcript (CARTPT) expression with follicle health status and inhibitory effects of the mature CARTPT peptide (CART) on FSH signal transduction in vitro resulting in reduced bovine granulosa cell CYP19A1 mRNA and estradiol production. The objectives of this study were to investigate temporal regulation of granulosa cell CARTPT expression (granulosa cell mRNA and follicular fluid CART peptide concentrations) during follicular waves, CART regulation of androstenedione production (precursor for estradiol biosynthesis) by thecal tissue collected at specific stages of a follicular wave, FSH regulation of granulosa cell CARTPT mRNA expression and the ability of CART to inhibit granulosa cell estradiol production and CYP19A1 mRNA expression when administered in vivo. CART concentrations in healthy estrogen active follicles (estradiol > progesterone in follicular fluid) decreased after dominant follicle selection and CARTPT mRNA was lower in healthy estrogen active versus estrogen inactive atretic follicles (progesterone > estradiol) collected at the predeviation and early dominance stages. CART treatment reduced LH-induced androstenedione production by thecal tissue collected at pre deviation and early dominance stages, but not at later stages of a follicular wave. FSH or IGF1 treatment in vitro reduced granulosa cell CARTPT mRNA in a dose dependent fashion. Administration of CART in vivo into follicles at the early dominance stage reduced follicular fluid estradiol concentrations and granulosa cell CYP19A1 mRNA. Collectively, results support a potential stage specific regulatory role for CART in negative regulation of estradiol production associated with selection of the dominant follicle.
COCAINE- AND AMPHETAMINE-REGULATED TRANSCRIPT (CART) ACCELERATES TERMINATION OF FSH-INDUCED ERK1/2 AND AKT ACTIVATION BY REGULATING THE EXPRESSION AND DEGRADATION OF SPECIFIC MAP KINASE PHOSPHATASES IN BOVINE GRANULOSA CELLS. Sen A et al. Pleiotropic actions of CART are well described in the central nervous system and periphery but the intracellular mechanisms mediating biological actions of CART are poorly understood. Although CART is not expressed in mouse ovaries, we have previously established CART as a novel intracellular regulator of estradiol production in bovine granulosa cells. We demonstrated that inhibitory actions of CART on estradiol production are mediated through inhibition of FSH-induced cAMP accumulation, Ca(2+) influx and aromatase mRNA expression via a Go/i dependent pathway. We also reported that FSH-induced estradiol production is dependent on Erk1/2 and Akt signaling and CART may regulate other signaling proteins downstream of cAMP essential for estradiol production. Here, we demonstrate that CART is a potent inhibitor of FSH-stimulated Erk1/2 and Akt signaling and the mechanisms involved. Transient CART stimulation of bovine granulosa cells shortens the duration of FSH-induced Erk1/2 and Akt signaling while a prolonged (24 h) CART treatment blocks Erk1/2 and Akt activation in response to FSH. This CART-induced accelerated termination of Erk1/2 and Akt signaling is mediated both by induced expression and impaired ubiquitin-mediated proteasome degradation of dual specific phosphatase 5 (DUSP5) and protein phosphatase 2A (PP2A). Results also support existence of a negative feedback loop where CART via a Go/i-MEK dependent pathway activates Erk1/2 and the latter induces DUSP5 expression. Moreover, siRNA mediated ablation of DUSP5 and/or PP2A prevents the CART-induced early termination of Erk1/2 and Akt signaling. Results provide novel insight into the intracellular mechanism of action of CART in regulation of FSH-induced MAP kinase signaling.
Evidence of a local negative role for cocaine and amphetamine regulated transcript (CART), inhibins and low molecular weight insulin like growth factor binding proteins in regulation of granulosal cell estradiol production during follicular waves in cattle. Kobayashi Y et al. ABSTRACT: The ability of ovarian follicles to produce large amounts of estradiol is a hallmark of follicle health status. Estradiol producing capacity is lost in ovarian follicles before morphological signs of atresia. A prominent wave like pattern of growth of antral follicles is characteristic of monotocous species such as cattle, horses and humans. While our knowledge of the role of pituitary gonadotropins in support of antral follicle growth and development is well established, the intrinsic factors that suppress estradiol production and may help promote atresia during follicular waves are not well understood. Numerous growth factors and cytokines have been reported to suppress granulosa cell estradiol production in vitro, but the association of expression of many such factors in vivo with follicle health status and their physiological significance are not clear. The purpose of this review is to discuss the in vivo and in vitro evidence supporting a local physiological role for cocaine and amphetamine regulated transcript, inhibins and low molecular weight insulin like growth factor binding proteins in negative regulation of granulosa cell estradiol production, with emphasis on evidence from the bovine model system.
Cocaine- and Amphetamine-Regulated Transcript (CART) Regulation of Follicle Stimulating Hormone Signal Transduction in Bovine Granulosa Cells. Sen A et al. Regulation of estradiol production, central to ovarian follicular development and reproductive function, is mediated by a complex interaction of pituitary gonadotropins such as FSH with locally produced regulatory molecules. We have previously demonstrated a negative association of expression of Cocaine-and Amphetamine-Regulated Transcript (CART) with follicle health status and a novel local negative role for CART in regulation of basal estradiol production by bovine granulosa cells. However, effects of CART on FSH-induced estradiol production and the underlying mechanism(s) mediating the physiological actions of CART on granulosa cells are not known. Objectives of the present study were to determine effects of CART on basal and FSH-induced intracellular cAMP levels, aromatase mRNA, estradiol accumulation, calcium signaling and the intracellular signaling pathways involved using primary cultures of bovine granulosa cells. CART treatment potently inhibits the FSH-induced rise in granulosa cell cAMP levels, estradiol accumulation and aromatase mRNA. Furthermore, results show that calcium is essential for FSH-induced cAMP and estradiol accumulation and CART significantly inhibits FSH-induced calcium influx. Select G-protein and protein kinase inhibitors were used to elucidate pathways involved in CART actions. The inhibitory actions of CART on FSH signaling and estradiol production are mediated via a Go/i-dependent pathway, while none of the other signaling inhibitors had any effect on CART actions. Results demonstrate novel potent inhibitory effects of CART on multiple components of the FSH signaling pathway linked to estradiol production and follicular development and shed new insight into the mechanism of action of CART potentially pertinent within and beyond the reproductive system.
Cocaine- and Amphetamine-Regulated Transcript (CART) Regulation of Follicle Stimulating Hormone Signal Transduction in Bovine Granulosa Cells. Sen A et al. Regulation of estradiol production, central to ovarian follicular development and reproductive function, is mediated by a complex interaction of pituitary gonadotropins such as FSH with locally produced regulatory molecules. We have previously demonstrated a negative association of expression of Cocaine-and Amphetamine-Regulated Transcript (CART) with follicle health status and a novel local negative role for CART in regulation of basal estradiol production by bovine granulosa cells. However, effects of CART on FSH-induced estradiol production and the underlying mechanism(s) mediating the physiological actions of CART on granulosa cells are not known. Objectives of the present study were to determine effects of CART on basal and FSH-induced intracellular cAMP levels, aromatase mRNA, estradiol accumulation, calcium signaling and the intracellular signaling pathways involved using primary cultures of bovine granulosa cells. CART treatment potently inhibits the FSH-induced rise in granulosa cell cAMP levels, estradiol accumulation and aromatase mRNA. Furthermore, results show that calcium is essential for FSH-induced cAMP and estradiol accumulation and CART significantly inhibits FSH-induced calcium influx. Select G-protein and protein kinase inhibitors were used to elucidate pathways involved in CART actions. The inhibitory actions of CART on FSH signaling and estradiol production are mediated via a Go/i-dependent pathway, while none of the other signaling inhibitors had any effect on CART actions. Results demonstrate novel potent inhibitory effects of CART on multiple components of the FSH signaling pathway linked to estradiol production and follicular development and shed new insight into the mechanism of action of CART potentially pertinent within and beyond the reproductive system.
Expression regulated by
Growth Factors/ cytokines, leptin
Comment
Gestational Diabetes Epigenetically Reprograms the Cart Promoter in Fetal Ovary Causing Sub-Fertility in Adult Life. Sinha N et al. (2019) Intra-uterine exposure to various adverse conditions during fetal development can lead to epigenetic changes in fetal tissues, predisposing those tissues to disease conditions later in life. An example is gestational diabetes (GD), where the offspring has a higher risk of developing obesity, metabolic disorders or cardiovascular disease in adult life. In this study, using two well-established GD (streptozotocin- and high fat-high sugar-induced) mouse models, we report that female offspring from GD dams are predisposed towards fertility problems later in life. This predisposition to fertility problems is due to altered ovarian expression of a peptide called Cocaine-and Amphetamine-Regulated Transcript (CART), that is known to negatively affect folliculogenesis and is induced by elevated leptin levels. Results show that the underlying cause of this altered expression is due to fetal epigenetic modifications involving glucose- and insulin-induced micro-RNA, miR-101, and PI3K/Akt pathway. These signaling events regulate Ezh2, a histone methyltransferase that promotes H3K27me3, a gene repressive mark, and CBP/p300, a histone acetyltransferase that promotes H3K27ac, a transcription activation mark, in the fetal ovary. Moreover, the CART promoter has depleted 5-methylcytosine (5mC) and enriched 5-hydroxymethylcytosine (5hmC) levels. The depletion of H3K27me3 and 5mC repressive marks and subsequent increase in H3K27ac and 5hmC gene activating marks convert the Cartpt promoter to a "super-promoter". This makes the Cartpt promoter more sensitive to leptin levels that predispose the GD offspring to fertility problems. Therefore, this study provides a novel mechanistic insight about fetal epigenome reprogramming that manifests to ovarian dysfunction and subfertility later in adult life.//////////////////
Leptin-induced CART (Cocaine-and Amphetamine-Regulated Transcript) is a novel intra-ovarian mediator of obesity-related infertility in females. Ma X et al. (2016) Obesity is considered detrimental to women's reproductive health. Although most of the attention has been focused on the effects of obesity on hypothalamic function, studies suggest a multifactorial impact. In fact, obesity is associated with reduced fecundity even in women with regular cycles, indicating that there may be local ovarian effects modulating fertility. Here we describe a novel mechanism for leptin actions directly in the ovary that may account for some of the negative effects of obesity on ovarian function. We find that normal cycling, obese, hyperleptinemic mice fed with a high fat diet are sub-fertile and ovulate fewer oocytes compared to animals fed with a normal diet. Importantly, we show that leptin induces expression of the neuropeptide Cocaine-and Amphetamine-Regulated Transcript (CART) in the granulosa cells of ovarian follicles both in vitro and in vivo. CART then negatively affects intra-cellular cAMP levels, MAPK signaling, and aromatase gene expression, which leads to lower estradiol synthesis in granulosa cells and altered ovarian folliculogenesis. Finally, in human samples from patients undergoing in vitro fertilization, we show a significant positive correlation between patient BMI, CART mRNA expression in granulosa cells, and CART peptide levels in follicular fluid. These observations suggest that, under obese conditions, CART acts as a local mediator of leptin in the ovary to cause ovarian dysfunction and reduced fertility.//////////////////
Ovarian localization
Oocyte, Cumulus, Granulosa
Comment
Kobayashi Y et al obtained evidence that cocaine and amphetamine regulated transcript (CART), a potent anorectic neuropeptide, is expressed in the bovine ovary. Objectives of this study were to characterize bovine ovarian CART and determine its localization, regulation, and regulatory role during follicular development. CART mRNA was detected in stroma of adult ovaries and in large follicles, but was undetectable in several peripheral tissues, fetal ovaries and corpora lutea. Within the ovary, CART mRNA and peptide were localized to the granulosal layer of some but not all antral follicles, with low but detectable expression in oocytes and cumulus cells. CART mRNA was undetectable in granulosal cells of dominant ovulatory follicles collected before and after the preovulatory gonadotropin surge, but was detected in the granulosal layer of adjacent subordinate follicles. In addition, amounts of CART mRNA and follicular fluid concentrations of CART peptide were greater in subordinate follicles vs. dominant follicles of the first follicular wave. Furthermore, CART treatment inhibited basal estradiol production, but not progesterone production by granulosal cells in a dose-dependent fashion and the effect was dependent on stage of cell differentiation. We conclude that granulosal cell CART expression is temporally regulated and potentially associated with follicle health status and CART can inhibit granulosal cell estradiol production. Thus, CART may be a novel local regulator of follicular atresia in the bovine ovary. Izhar
Follicle stages
Comment
Generation of a bovine oocyte cDNA library and microarray: resources for identification of genes important for follicular development and early embryogenesis Yao J, et al .
The oocyte is a key regulator of ovarian folliculogenesis and early embryonic development. However, the composition of the oocyte transcriptome and identities and functions of key oocyte-specific genes involved in the above processes are relatively unknown. Using a PCR-based cDNA amplification method (SMART technology), we constructed a bovine oocyte cDNA library. Analysis of 230 expressed sequence tags (ESTs) from this library identified 102 unique sequences. Although some correspond to housekeeping genes (e.g., ribosomal protein L15) and some represent genes previously known to be expressed in oocytes and other tissues, most encode for genes whose expression in mammalian oocytes has not been reported previously (e.g., cocaine- and amphetamine-regulated transcript) or genes of unknown function. Sixteen did not show significant sequence similarity to any entries in the GenBank database and were classified as novel. Using over 2,000 unsequenced, randomly selected cDNA clones from the library, we constructed an oocyte microarray and performed experiments to identify genes preferentially expressed in fetal ovary (an enriched source of oocytes) relative to somatic tissues. Eleven clones were identified by microarray analysis with consistently higher expression in fetal ovaries (collected from animals at days 210-260 of gestation) compared with spleen and liver. DNA sequence analysis of these clones revealed that two correspond to JY-1, a novel bovine oocyte-specific gene. The remaining nine clones represent five identified genes and one additional completely novel gene. Increased abundance of mRNA in fetal ovary for five of the six genes identified was confirmed by real-time PCR. Results demonstrate the potential utility of these unique resources for identification of oocyte-expressed genes potentially important for reproductive function.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: fertile Comment: Gender-specific increase of bone mass by CART peptide treatment is ovary-dependent. Gerrits H et al. Cocaine- and amphetamine-regulated transcript (CART) has emerged as a neurotransmitter and hormone that has been implicated in many processes including food intake, maintenance of body weight and reward, but also in the regulation of bone mass. CART-deficient mice are characterized by an osteoporotic phenotype, whereas female transgenic mice overexpressing CART display an increase in bone mass. Here we describe experiments that show that peripheral subcutaneous sustained release of different CART peptide isoforms for a period up to 60 days increased bone mass by 80% in intact mice. CART peptides increased trabecular bone mass, but not cortical bone mass, and the increase was caused by reduced osteoclast activity in combination with normal osteoblast activity. The observed effect on bone was gender specific, as male mice did not respond to treatment with CART peptides. In addition, male transgenic CART overexpressing mice did not display increased bone mass. Ovariectomy (OVX) completely abolished the increase of bone mass by CART peptides, both in CART peptide treated wild-type mice and in CART transgenic mice. The effect of CART peptide treatment on trabecular bone was not mediated by 17?estradiol (E(2) ) as supplementation of OVX mice with E(2) could not rescue the effect of CART peptides on bone. Together these results indicate that sustained release of CART peptides increases bone mass in a gender specific way via a yet unknown mechanism that requires the presence of the ovary. ? 2011 American Society for Bone and Mineral Research.