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insulin like growth factor 2 OKDB#: 864
 Symbols: IGF2 Species: human
 Synonyms: GRDF, IGF-II, PP9974, C11orf43  Locus: 11p15.5 in Homo sapiens

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General Comment 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
Comment Poretsky L, et al. 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
Comment 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
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.

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created: Feb. 19, 2000, midnight by: Giudice   email:
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last update: Jan. 26, 2016, 4:11 p.m. by: hsueh    email:

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