Insulin-like growth factors I and II, also known as somatomedin C and somatomedin A, respectively, are
single chain polypeptides which share an amino acid sequence homology of about 47% with insulin and
about 31% with relaxin and with them comprise the insulin family of polypeptide growth factors. Their
functions include mediation of growth hormone action, stimulation of growth of cultured cells, stimulation of the action
of insulin, and involvement in development and growth. They appear to be autocrine regulators of cell proliferation.
NCBI Summary:
This gene encodes a member of the insulin family of polypeptide growth factors, which are involved in development and growth. It is an imprinted gene, expressed only from the paternal allele, and epigenetic changes at this locus are associated with Wilms tumour, Beckwith-Wiedemann syndrome, rhabdomyosarcoma, and Silver-Russell syndrome. A read-through INS-IGF2 gene exists, whose 5' region overlaps the INS gene and the 3' region overlaps this gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2010]
General function
Ligand, Growth factor
Comment
IGF2 is a mitogen for many cell types and an important modulator of muscle growth and differentiation. The gene is
widely expressed during prenatal development and its activity is regulated by genomic imprinting, the gene being
inactive on the chromosome inherited from the mother in most normal tissues./////////Characterization of the IGF2 Imprinted Gene Methylation Status in Bovine Oocytes during Folliculogenesis. Mendonça Ados S et al. (2015) DNA methylation reprogramming occurs during mammalian gametogenesis and embryogenesis. Sex-specific DNA methylation patterns at specific CpG islands controlling imprinted genes are acquired during this window of development. Characterization of the DNA methylation dynamics of imprinted genes acquired by oocytes during folliculogenesis is essential for understanding the physiological and genetic aspects of female gametogenesis and to determine the parameters for oocyte competence. This knowledge can be used to improve in vitro embryo production (IVP), specifically because oocyte competence is one of the most important aspects determining the success of IVP. Imprinted genes, such as IGF2, play important roles in embryo development, placentation and fetal growth. The aim of this study was to characterize the DNA methylation profile of the CpG island located in IGF2 exon 10 in oocytes during bovine folliculogenesis. The methylation percentages in oocytes from primordial follicles, final secondary follicles, small antral follicles, large antral follicles, MII oocytes and spermatozoa were 73.74 ± 2.88%, 58.70 ± 7.46%, 56.00 ± 5.58%, 65.77 ± 5.10%, 56.35 ± 7.45% and 96.04 ± 0.78%, respectively. Oocytes from primordial follicles showed fewer hypomethylated alleles (15.5%) than MII oocytes (34.6%) (p = 0.039); spermatozoa showed only hypermethylated alleles. Moreover, MII oocytes were less methylated than spermatozoa (p<0.001). Our results showed that the methylation pattern of this region behaves differently between mature oocytes and spermatozoa. However, while this region has a classical imprinted pattern in spermatozoa that is fully methylated, it was variable in mature oocytes, showing hypermethylated and hypomethylated alleles. Furthermore, our results suggest that this CpG island may have received precocious reprogramming, considering that the hypermethylated pattern was already found in growing oocytes from primordial follicles. These results may contribute to our understanding of the reprogramming of imprinted genes during bovine oogenesis.//////////////////
Cellular localization
Secreted
Comment
Response of IGF and IL-6 to ovarian stimulation in PCOS and normal women. Liang FJ et al. (2009) The objective of the present study was to investigate the response patterns of insulin-like growth factors (IGFs) and interleukin-6 (IL-6) to ovarian stimulation within 24 h in patients with polycystic ovary syndrome (PCOS) in comparison with normally ovulating women. This controlled prospective clinical study involved 60 women who attended an infertility clinic. For the induction of the ovarian stimulation, fifty-two patients with PCOS and eight control cases were injected with human menopause gonadotropin (hMG) and human chorionic gonadotropin (hCG) during the early follicular phase of the natural or induced menstrual cycle. The blood was sampled before (0h) and 6, 12, 18, and 24 h after the stimulation. Serum levels of estradiol (E2), IGF-I, IGF-II and IL-6 were measured by radioimmunoassay. A significant decrease in serum IGF-II at 12 h was observed after a mixture of hMG and hCG was administered in patients with polycystic ovaries (PCO) including the typical PCOS group and the PCO + OA group (accumulated p < 0.05), while normal women presented a slight decrease (accumulated p < 0.1) 18h after the stimulation. Moreover, all the groups had similar serum levels of IL-6 and IGF-I at all time points. An increase in serum E2 occurred coincident with a decrease in IGF-II in all the groups except the ovarian hyperandrogenism patients (HA + OA group). Serum IGF-II levels, which appeared to be negatively correlated with elevated E2, statistically decreased in PCO patients early after hMG and hCG administration when monitored for 24 h, while no such changes were observed in IGF-I and IL-6.//////////////////
Ovarian function
Follicle development, Preantral follicle growth, Antral follicle growth, Follicle atresia, Steroid metabolism, Luteinization, Oogenesis, Early embryo development
Comment
IGF2 improves the developmental competency and meiotic structure of oocytes from aged mice. Muhammad T et al. (2020) Advanced maternal-age is a major factor adversely affecting oocyte quality, consequently worsening pregnancy outcomes. Thus, developing strategies to reduce the developmental defects associated with advanced maternal-age would benefit older mothers. Multiple growth factors involved in female fertility have been extensively studied; however, the age-related impacts of various growth factors remain poorly studied. In the present study, we identified that levels of insulin-like growth factor 2 (IGF2) are significantly reduced in the serum and oocytes of aged mice. We found that adding IGF2 in culture medium promotes oocyte maturation and significantly increases the proportion of blastocysts: from 41% in the untreated control group to 64% (50 nM IGF2) in aged mice (p < 0.05). Additionally, IGF2 supplementation of the culture medium reduced reactive oxygen species production and the incidence of spindle/chromosome defects. IGF2 increases mitochondrial functional activity in oocytes from aged mice: we detected increased ATP levels, elevated fluorescence intensity of mitochondria, higher mitochondrial membrane potentials, and increased overall protein synthesis, as well as increased autophagy activity and decreased apoptosis. Collectively, our findings demonstrate that IGF2 supplementation in culture media improves oocyte developmental competence and reduces meiotic structure defects in oocytes from aged mice.//////////////////
Articulation: a 2+2 nursing program success. Burger J et al. (1988)//////////////////Poretsky L, et al. $10453357] reviewed the insulin-related ovarian regulatory system in health and disease.
Giudice LC. reviewed the growth factor action on ovarian function in polycystic ovary syndrome.
Yuan W, et al. reported that insulin-like growth factor-II mediates the steroidogenic and growth promoting actions of follicle
stimulating hormone on human ovarian pre-antral follicles cultured in vitro.
Expression regulated by
FSH, LH, Growth Factors/ cytokines
Comment
Regulation of Insulin-Like Growth Factor 2 by Oocyte-Secreted Factors in Primary Human Granulosa Cells. Hobeika E et al. (2019) Human granulosa cells (hGCs) produce and respond to insulin-like growth factor 2 (IGF2) but whether the oocyte participates in IGF2 regulation in humans is unknown. To determine the role of oocyte-secreted factors (OSFs) such as growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) in IGF2 production by hGCs. Primary human cumulus GCs in culture. University infertility center. GCs of women undergoing in vitro fertilization. Cells treated with GDF9 and BMP15 in the presence of vehicle, FSH, dbcAMP, or SMAD inhibitors. Quantification of mRNA, protein, promoter activity, and DNA methylation. FSH-stimulation of IGF2 (protein and mRNA) was significantly potentiated by the GDF9 and BMP15 (G+B) combination (P<0.0001) in a concentration-dependent manner showing a maximal effect at five ng/ml each. However, GDF9 or BMP15 alone or in combination (G+B) have no effect on IGF2 in the absence of FSH. FSH stimulated IGF2 promoter 3 activity, but G+B had no effect on promoter activity. G+B potentiated IGF2 stimulation by cAMP. SMAD3 inhibitors inhibited G+B enhancement of IGF2 stimulation by FSH (P<0.05) but had no effect on FSH induction. Moreover, inhibition of insulin-like growth factor receptor partially blocked G+B potentiation of FSH actions (P<0.009). For the first time, we show that the oocyte actively participates in the regulation of IGF2 expression in hGCs, an effect that is mediated by the specific combination of G+B via SMAD2/3, which in turn target mechanisms downstream of the FSH receptor.//////////////////
FSH Regulates IGF2 Expression in Human Granulosa Cells in an AKT-dependent Manner. Baumgarten SC et al. (2015) IGF2 is highly expressed in the granulosa cells of human dominant ovarian follicles; however, little is known about the regulation of the IGF2 gene or the interaction of IGF2 and FSH during follicle development. To examine the mechanisms involved in the regulation of the IGF2 gene by FSH and the interplay between FSH and IGF2 during granulosa cell differentiation. Design, Setting, Patients, and Interventions: Cumulus granulosa cells were separated from cumulus-oocyte-complexes isolated from the follicular aspirates of IVF patients and cultured for in vitro studies. Protein and mRNA levels of IGF2 and CYP19A1 (aromatase) were quantified using Western blot and quantitative real-time PCR. IGF2 promoter-specific activation was determined by the amplification of alternative exons by PCR. Cell proliferation was assessed after treatment with FSH and/or IGF2. FSH significantly enhanced IGF2 expression after 8 hours of treatment and at low doses (1 ng/ml). Reciprocally, IGF2 synergized with FSH to increase cell proliferation and the expression of CYP19A1. When IGF2 activity was blocked, FSH was no longer able to stimulate CYP19A1 expression. Determination of IGF2 promoter usage in human cumulus cells showed that the IGF2 gene is driven by promoters P3 and P4. However, FSH exclusively increased P3 promoter derived transcripts. Moreover, the FSH-induced stimulation of P3-driven IGF2 transcripts was blocked by co-treatment with inhibitors of AKT or IGF1R. The inhibitory effect of the IGF1R inhibitor on FSH-induced IGF2 mRNA accumulation was reversed by overexpression of a constitutively active AKT construct. FSH is a potent enhancer of IGF2 expression in human granulosa cells. In return, IGF2 activation of the IGF1R and AKT is required for FSH to stimulate CYP19A1 expression and proliferation of granulosa cells. These findings suggest a positive loop interaction between FSH and IGF2 that is critical for human granulosa cell proliferation and differentiation.//////////////////
Ovarian localization
Granulosa, Theca, Luteal cells
Comment
el-Roeiy A, et al. reported the expression of the genes encoding the insulin-like growth factors (IGF-I and II), the IGF and insulin
receptors, and IGF-binding proteins-1-6 and the localization of their gene products in normal and
polycystic ovary syndrome ovaries.
Follicle stages
Secondary, Antral, Preovulatory, Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
2 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment:DeChiara et al. (1991) produced targeted disruption of the Igf2 gene in mice by homologous recombination in ES cells.
Transmission of this mutation through the male germline resulted in heterozygous progeny that were growth deficient. In
contrast, when the disrupted gene was transmitted maternally, the heterozygous offspring were phenotypically normal.
Homozygous mutants were indistinguishable in appearance from growth-deficient heterozygous sibs.
Species: mouse
Mutation name: None
type: targeted overexpression fertility: embryonic lethal Comment:Sun et al. (1997) introduced Igf2 transgenes into
the mouse genome by using embryonic stem (ES) cells and thereby caused transactivation of the endogenous Igf2 gene.
The consequent overexpression of Igf2 resulted in most of the symptoms of Beckwith-Wiedemann syndrome (BWS), including
prenatal overgrowth, polyhydramnios, fetal and neonatal lethality, disproportionate organ overgrowth including tongue
enlargement, and skeletal abnormalities. This was presented as evidence that IGF2 overexpression is a key determinant
of BWS.