RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.

Huaibiao Li,Aspasia Ploubidou,Stéphane Brunet,Heike Heuer,Marie-Hélène Verlhac,Jürgen Moll,Peter Herrlich,Lucien Frappart,Jana Hamann,Torsten Kroll,Anne Winkler

doi:10.1242/bio.201410892

Abstract

The postnatal mammalian ovary contains the primary follicles, each comprising an immature oocyte surrounded by a layer of somatic granulosa cells. Oocytes reach meiotic and developmental competence via folliculogenesis. During this process, the granulosa cells proliferate massively around the oocyte, form an extensive extracellular matrix (ECM) and differentiate into cumulus cells. As the ECM component hyaluronic acid (HA) is thought to form the backbone of the oocyte-granulosa cell complex, we deleted the relevant domain of the Receptor for HA Mediated Motility (RHAMM) gene in the mouse. This resulted in folliculogenesis defects and female hypofertility, although HA-induced signalling was not affected. We report that wild-type RHAMM localises at the mitotic spindle of granulosa cells, surrounding the oocyte. Deletion of the RHAMM C-terminus in vivo abolishes its spindle association, resulting in impaired spindle orientation in the dividing granulosa cells, folliculogenesis defects and subsequent female hypofertility. These data reveal the first identified physiological function for RHAMM, during oogenesis, and the importance of this spindle-associated function for female fertility.

Highlights

The postnatal mammalian ovary contains primary oocytes, each enclosed in a single layer of somatic granulosa cells, forming the so-called primordial ovarian follicles (Pepling and Spradling, 2001)
Receptor for HA Mediated Motility (RHAMM) mRNA was highly expressed along the mitotic epithelium of the uterus, as well as in distinct foci within the ovary that correspond to the ovarian follicles (Fig. 1A)
The hmmrm/m mouse expresses C-terminus truncated RHAMM, devoid of the centrosome-targeting and hyaluronic acid (HA)-binding protein domains The functions of RHAMM, far described in cultured cells, are mediated by its centrosome-targeting and HA-binding domains, which are located in the C-terminus (Fig. 2B) and are responsible for the spindle assembly and cell migration roles of the protein, respectively

Summary

Introduction

The postnatal mammalian ovary contains primary oocytes, each enclosed in a single layer of somatic granulosa cells, forming the so-called primordial ovarian follicles (Pepling and Spradling, 2001). These immature oocytes, which are arrested in prophase of Meiosis I (Eppig, 1993), acquire meiotic and developmental competence during folliculogenesis, i.e. the transition from the small primordial follicle to the large multilayered pre-ovulatory. The fully-grown oocyte is tightly enclosed into several layers of thousands of cumulus cells, held together by gap junctions and stabilized by extensive ECM This is called the cumulus-oocyte complex (reviewed by Russell and Salustri, 2006). The cumulus-oocyte association is retained through ovulation, whereupon the follicle wall ruptures releasing the complex

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