Insulin Receptor and IGF1R Are Not Required for Oocyte Growth, Differentiation, and Maturation in Mice

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.

[1]  Michael T. McManus,et al.  Sertoli cell Dicer is essential for spermatogenesis in mice. , 2009, Developmental biology.

[2]  A. Efstratiadis,et al.  The hormonal action of IGF1 in postnatal mouse growth , 2008, Proceedings of the National Academy of Sciences.

[3]  H. Fan,et al.  Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. , 2008, Molecular endocrinology.

[4]  A. Cooney,et al.  Oocyte-Specific Deletion of Pten Causes Premature Activation of the Primordial Follicle Pool , 2008, Science.

[5]  P. Gonçalves,et al.  Effect of angiotensin II with follicle cells and insulin-like growth factor-I or insulin on bovine oocyte maturation and embryo development. , 2006, Theriogenology.

[6]  R. Klein,et al.  Role of brain insulin receptor in control of body weight and reproduction. , 2006, Science.

[7]  R. van den Hurk,et al.  Formation of mammalian oocytes and their growth, differentiation and maturation within ovarian follicles. , 2005, Theriogenology.

[8]  A. Cooney,et al.  Differential Oocyte-Specific Expression of Cre Recombinase Activity in GDF-9-iCre, Zp3cre, and Msx2Cre Transgenic Mice1 , 2004, Biology of reproduction.

[9]  A. Bartke,et al.  The Consequences of Altered Somatotropic System on Reproduction1 , 2004, Biology of reproduction.

[10]  J. Dupont,et al.  Biology of insulin-like growth factors in development. , 2003, Birth defects research. Part C, Embryo today : reviews.

[11]  D. Accili,et al.  Testis determination requires insulin receptor family function in mice , 2003, Nature.

[12]  R. DePinho,et al.  Suppression of Ovarian Follicle Activation in Mice by the Transcription Factor Foxo3a , 2003, Science.

[13]  C. Wrenzycki,et al.  Mitogenic and anti-apoptotic activity of insulin on bovine embryos produced in vitro. , 2003, Reproduction.

[14]  Y. Kido,et al.  Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. , 2002, The Journal of clinical investigation.

[15]  J. Eppig,et al.  Oocyte control of ovarian follicular development and function in mammals. , 2001, Reproduction.

[16]  C. Bondy,et al.  Granulosa cell proliferation is impaired in the Igf1 null ovary. , 2001, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[17]  E. Hafen,et al.  An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control , 2001, Current Biology.

[18]  S. Xuan,et al.  Conditional mutagenesis in mice with heat shock promoter-driven cre transgenes , 2000, Mammalian Genome.

[19]  E. Hafen,et al.  Autonomous Control of Cell and Organ Size by CHICO, a Drosophila Homolog of Vertebrate IRS1–4 , 1999, Cell.

[20]  C. Kahn,et al.  A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. , 1998, Molecular cell.

[21]  B. Conne,et al.  Masking, unmasking, and regulated polyadenylation cooperate in the translational control of a dormant mRNA in mouse oocytes. , 1998, Genes & development.

[22]  M. Matzuk,et al.  Insulin-like growth factor I regulates gonadotropin responsiveness in the murine ovary. , 1997, Molecular endocrinology.

[23]  D. Accili,et al.  Growth-promoting interaction of IGF-II with the insulin receptor during mouse embryonic development. , 1997, Developmental biology.

[24]  T. Ludwig,et al.  Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. , 1996, Developmental biology.

[25]  J. Baker,et al.  Effects of an Igf1 gene null mutation on mouse reproduction. , 1996, Molecular endocrinology.

[26]  B. Lamothe,et al.  Targeted disruption of the insulin receptor gene in the mouse results in neonatal lethality. , 1996, The EMBO journal.

[27]  J. Tarín,et al.  Oocyte maturation in humans: The role of gonadotropins and growth factors , 1994, Fertility and sterility.

[28]  H. Matsuo,et al.  Insulin receptor expression in follicular and stromal compartments of the human ovary over the course of follicular growth, regression and atresia. , 1993, Endocrine journal.

[29]  J. Baker,et al.  Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) , 1993, Cell.

[30]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[31]  C. Bondy,et al.  Anatomy of the human ovarian insulin-like growth factor system. , 1993, Biology of reproduction.

[32]  E. Adashi,et al.  Expression of the insulin-like growth factor (IGF)-I and -II and the IGF-I and -II receptor genes during postnatal development of the rat ovary. , 1992, Endocrinology.

[33]  C. Bondy,et al.  Cellular pattern of insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the developing and mature ovarian follicle. , 1991, Endocrinology.

[34]  J. Cara,et al.  Insulin-like growth factor I and insulin potentiate luteinizing hormone-induced androgen synthesis by rat ovarian thecal-interstitial cells. , 1988, Endocrinology.

[35]  D. Belin,et al.  Plasminogen activator in mouse and rat oocytes: Induction during meiotic maturation , 1985, Cell.

[36]  D. Belin,et al.  Concomitant secretion of prourokinase and of a plasminogen activator- specific inhibitor by cultured human monocytes-macrophages , 1984, The Journal of experimental medicine.

[37]  C. Finch,et al.  A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology. , 1982, Biology of reproduction.

[38]  A. Granelli‐Piperno,et al.  A study of proteases and protease-inhibitor complexes in biological fluids , 1978, The Journal of experimental medicine.

[39]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[40]  T. Pedersen,et al.  Proposal for a classification of oocytes and follicles in the mouse ovary. , 1968, Journal of reproduction and fertility.

[41]  T. Nagai,et al.  Possible mechanism for acceleration of meiotic progression of bovine follicular oocytes by growth factors in vitro. , 2002, Reproduction.

[42]  Y. Kido,et al.  Defective insulin secretion in pancreatic beta cells lacking type 1 IGF receptor. , 2002, The Journal of clinical investigation.

[43]  Philippe Soriano.  Generalized lacZ expression with the ROSA26 Cre reporter strain , 1999, Nature Genetics.

[44]  A. Efstratiadis.  Genetics of mouse growth. , 1998, The International journal of developmental biology.

[45]  Mark D. Johnson,et al.  Early neonatal death in mice homozygous for a null allele of the insulin receptor gene , 1996, Nature Genetics.

[46]  P. Chambon,et al.  Estrogen Receptor (cid:1) Is a Major Contributor to Estrogen-Mediated Fetal Testis Dysgenesis and Cryptorchidism , 2007 .