Biol Reprod Keystone Symposia Conference on Frontiers in Reproductive Biology & Regulation of Fertility.
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BOR - Papers in Press, published online ahead of print February 28, 2007.
Biol Reprod 2007, 10.1095/biolreprod.106.059360
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Submitted December 7, 2006
Returned for revision December 23, 2006
Accepted February 19, 2007

Ovary


Role of Central Nervous System and Ovarian Insulin Receptor Substrate 2 Signaling in Female Reproductive Function in the Mouse

Irina Neganova , Hind Al-Qassab , Helen Heffron , Colin Selman , Agharul I. Choudhury , Steven Lingard , Ivan Diakonov , Michael Patterson , Mohammad Ghatei , Stephen R. Bloom , Stephen Franks , Ilpo Huhtaniemi , Kate Hardy , and Dominic J. Withers *

* To whom correspondence should be addressed. E-mail: d.withers{at}ucl.ac.uk.

Abstract
Insulin receptor signalling regulates female reproductive function acting in the central nervous system and ovary. Female mice globally lacking insulin receptor substrate (IRS) 2, a key mediator of insulin receptor action are infertile with defects in hypothalamic and ovarian function. To unravel the tissue-specific roles of IRS2 we examined reproductive function in female mice which lack Irs2 only in neurons. Surprisingly, these animals had minimal defects in pituitary and ovarian hormone levels, ovarian anatomy and function and breeding performance indicating that central nervous system IRS2 is not an obligatory signaling component regulating reproductive function. We therefore undertook detailed analysis of ovarian function in a novel Irs2 global null mouse line. Comparative morphometric analysis showed reduced follicle size, increased numbers of atretic follicles and impaired oocyte growth and antral cavity development in Irs2 null ovaries. Granulosa cell proliferation was also defective in Irs2 null ovaries. Furthermore insulin and eCG-stimulated phosphoinositide-3-OH kinase signaling events including phosphorylation of Akt/protein kinase B and glycogen synthase kinase 3-beta were impaired but MAP kinase signalling was preserved in Irs2 null ovaries. These abnormalities were associated with reduced expression of cyclin D2 and increased CDKN1B levels, demonstrating dysregulation of key components of the cell cycle apparatus implicated in ovarian function. Our data suggest that ovarian rather than central nervous system IRS2 signalling is important in the regulation of female reproductive function.

Key words: Ovary • Insulin • Insulin-like growth factor receptor • Kinases • Oocyte development


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