This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival.
Follicle development, Early embryo development
IGF1R signaling is necessary for FSH-induced activation of AKT and differentiation of human cumulus granulosa cells. Baumgarten SC 2014 et al.
Context: Follicle-stimulating hormone (FSH) is routinely administered to in vitro fertilization (IVF) patients to induce follicle maturation. During this process, granulosa cells differentiate and acquire specific functional characteristics that are required to coordinate ovulation and oocyte maturation. Objective: To gain insight into the molecular mechanisms regulating human granulosa cell differentiation. Design, Setting, Patients, and Interventions: Cumulus and mural granulosa cells were isolated from the follicular aspirates of IVF patients and analyzed immediately or cultured in serum-free media in the presence of FSH, insulin-like growth factors (IGF), or an inhibitor of type I IGF receptor (IGF1R) activity. Main outcome: We quantified messenger RNA and protein levels of steroidogenic enzymes, components of the IGF system, and gonadotropin receptors, measured 17-estradiol levels, and examined the activation of intracellular signaling pathways to assess granulosa cell differentiation as well as FSH and IGF actions in both cumulus and mural cells. Results: In freshly isolated cells, luteinizing hormone receptor (Lhr) and steroidogenic acute regulator (Star) were expressed at lower levels in cumulus than mural cells, whereas FSH receptor (Fshr) and anti-M )llerian hormone (Amh) were expressed at higher levels in cumulus than mural cells. In vitro, the expression of Igf2, the differentiation markers Lhr, Star, and Cyp19a1 (aromatase) as well as 17-estradiol production remained low in untreated cumulus cells but increased significantly after FSH treatment. Strikingly, this stimulatory effect of FSH was abolished by the inhibition of IGF1R activity. FSH-induced activation of v-akt murine thymoma viral oncogene homolog 3 (AKT) required IGF1R activity, and overexpression of constitutively active AKT rescued the induction of differentiation markers and 17-estradiol production by FSH in the presence of the IGF1R inhibitor. Conclusions: The cumulus cell response to FSH resembles the differentiation of preantral to preovulatory granulosa cells. This differentiation program requires IGF1R activity and subsequent AKT activation.
IGF-I Signaling Is Essential for FSH Stimulation of AKT and Steroidogenic Genes in Granulosa Cells. Zhou P et al. FSH and IGF-I synergistically stimulate gonadal steroid production; conversely, silencing the FSH or the IGF-I genes leads to infertility and hypogonadism. To determine the molecular link between these hormones, we examined the signaling cross talk downstream of their receptors. In human and rodent granulosa cells (GCs), IGF-I potentiated the stimulatory effects of FSH and cAMP on the expression of steroidogenic genes. In contrast, inhibition of IGF-I receptor (IGF-IR) activity or expression using pharmacological, genetic, or biochemical approaches prevented the FSH- and cAMP-induced expression of steroidogenic genes and estradiol production. In vivo experiments demonstrated that IGF-IR inactivation reduces the stimulation of steroidogenic genes and follicle growth by gonadotropins. FSH or IGF-I alone stimulated protein kinase B (PKB), which is also known as AKT and in combination synergistically increased AKT phosphorylation. Remarkably, blocking IGF-IR expression or activity decreased AKT basal activity and abolished AKT activation by FSH. In GCs lacking IGF-IR activity, FSH stimulation of Cyp19 expression was rescued by overexpression of constitutively active AKT. Our findings demonstrate, for the first time, that in human, mouse, and rat GCs, the well-known stimulatory effect of FSH on Cyp19 and AKT depends on IGF-I and on the expression and activation of the IGF-IR.
Embryotropic effect of insulin-like growth factor (IGF)-I and its receptor on development of porcine preimplantation embryos produced by in vitro fertilization and somatic cell nuclear transfer Kim S, et al .
Insulin-like growth factor (IGF)-I is a receptor-mediated autocrine/paracrine growth/survival factor for mammalian embryo development. The present study investigated the temporal expression and regulation of porcine IGF-I receptor (IGF-IR) mRNA and the role of IGF-I on development of porcine in vitro fertilized (IVF) and somatic cell nuclear transfer (SCNT) embryos. As assessed by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), the level of IGF-IR mRNA expression was high in unfertilized oocytes, 2-cell and 4-cell embryos and gradually decreased in 8-cell embryos, morulae, and blastocysts in both IVF and SCNT series. The IVF or SCNT embryos were cultured with 0, 1, 10, 50, or 100 ng/ml IGF-I for 168 hr. Supplementing with 50 ng/ml IGF-I increased blastocyst formation and the number of cells in inner cell masses (ICMs) in both IVF and SCNT embryos. In a second experiment, more blastocysts were obtained when IVF or SCNT embryos were cultured for the first 48 hr or for the entire 168 hr with 50 ng/ml IGF-I compared to culturing without IGF-I for 48 hr or with IGF-I for the last 120 hr or without IGF-I for the entire 168 hr. Treating IVF or SCNT embryos with 50 ng/ml IGF-I significantly up-regulated IGF-IR mRNA compared to untreated control embryos. In conclusion, the present study demonstrated that IGF-IR mRNA is expressed in porcine IVF and SCNT embryos, and that IGF-I improved the developmental competence of IVF and SCNT embryos through its specific receptors.
The beneficial effects of insulin and metformin on in vitro developmental potential of porcine oocytes and embryos Lee MS, et al .
Expression regulated by
Oocyte, Granulosa, Theca, Luteal cells
Expression of IGF receptors and its ligands in bovine oocytes and preimplantation embryos. Wang LM et al. The objectives of this study were to assess the mRNA expression and protein location of IGF receptors and its ligands in bovine oocytes and different stages of preimplantation embryos, and then evaluate the effect of different concentrations of IGF-II when added to either the maturation or culture medium on in vitro embryo development. For the assessment of mRNA expression by RT-PCR three replicates each of 100 oocytes, and 60 embryos at each of the 2-cell, 8-cell, morula and blastocyst stages of development were used. Immunocytochemical techniques were used to study the location of IGFs and their receptors for COC, oocytes, and embryos at the same stages of development (n=25). The effect of supplementing maturation medium with IGF-II was examined using groups of 20 oocytes exposed to 0 (control), 10, 20, 50 or 100ng IGF-II/ml medium. Each treatment was replicated five times. To study the effect of IGF-II added to culture medium, groups of 10 zygotes were cultured in the presence of 0 (control), 50, 100 or 150ng IGF-II/ml medium and the treatments replicated four times. The results showed that IGF-I mRNA could not be detected but IGF-II, IGF-IR and IGF-IIR mRNA existed in bovine preimplantation embryos. Proteins for IGF-II, IGF-IR and IGF-IIR were detected on the cell plasma membrane of cumulus cells of COC, immature and mature oocytes, and 2-cell stage embryos. They were observed in blastomere cytoplasm of 8-cell and morula stage embryos. In blastocysts, the IGF proteins were distributed in the trophectoderm but not in the inner cell mass. Adding 20ng/ml IGF-II to maturation medium resulted in higher rates of post-fertilization development than control at 8-cell (58.2% versus 44.5%; p<0.05) and blastocyst (37.0% versus 25.0%; p<0.05) stages of development; and the number of viable cells per blastocyst were significantly higher (126+/-6 versus 103+/-5; p<0.05). When IGF-II was added to the culture medium, no significant treatment differences were observed at 8-cell embryo stage but the development rate of zygotes cultured in the presence of 100ng IGF-II/ml medium to blastocysts was significantly higher than that of control (30.0% versus 19.2%; p<0.05). It was concluded that supplementation of in vitro maturation or culture media with IGF-II affects the development of bovine embryos and could be used to improve in vitro embryo production.
Zhao J, et al. (2002)reported that Immunoreactive IGF-I and IGFR was also visible in the pre-antral follicles, especially in the oocytes. Schams D, et al. (2002) A relative high expression of IGF-1 in theca interna (TI) was observed before selection (E<0.5ng/mL). In GC, mRNA expression increased after selection. In contrast, IGF-2 was mainly expressed in the TI. The IGFR-1 mRNA was present in the TI and GC with increasing levels during final development. The expression results were confirmed by localization of IGF-1 and IGFR-1 proteins in GC and TI. There is clear evidence for the local expression of IGFBPs in TI and GC compartment with clear regulatory differences. In CL, the highest mRNA expression of IGF-1, IGF-2 and IGFR-1 was observed during early luteal phase, followed by a decrease, and then by a tendency of an increase during the mid and late luteal phases of the cyclic CL. This level remained low during pregnancy. Intense immunostaining for IGFR-1 in CL was observed mainly in large luteal cells. Evidence for a mRNA for all six IGFBPs were obtained with distinct differences for BP-3, -4 and -5. In conclusion, this comprehensive study gives clear evidence for an important role of the IGFs and IGFBPs in bovine follicular development and CL function. The relative amounts of IGFBPs may ultimately determine ovarian IGF action.
Antral, Preovulatory, Corpus luteum
Mutation name: None
type: null mutation fertility: fertile Comment: Insulin Receptor and IGF1R Are Not Required for Oocyte Growth, Differentiation, and Maturation in Mice. Pitetti JL et al. In mammals, insulin and insulin-like growth factors (IGFs: IGF1 and IGF2) act through 2 structurally related receptors, the insulin receptor (INSR) and the type 1 IGF receptor (IGF1R), both of which are expressed in developing oocytes. IGF1 plays an important role in female reproduction, and female Igf1 knockout mice fail to ovulate and are infertile. On the other hand, little is known about the in vivo role of the insulin signaling pathway in oocytes during follicular development, although exposure to insulin or IGF1 in vitro improves oocyte maturation. To further address the significance of insulin/IGF signaling, we used conditional mutant mice and ablated the function of the genes encoding INSR, IGF1R, or both receptors specifically in developing mouse oocytes. Our genetic evidence showed unexpectedly that the female reproductive functions are not affected when Insr, Igf1r or both Insr;Igf1r are ablated in oocytes, as the female mice are fertile and exhibit normal estrous cyclicity, oocyte development and maturation, parturition frequency, and litter size. In view of these novel observations indicating that the insulin/IGF signaling is not essential in oocytes, the IGF1-dependent female fertility is re-evaluated and discussed.