RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.
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.
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.
Huaibiao
H
Li
Forschungszentrum Karlsruhe, Institut für Toxicologie und Genetik, Postfach 3640, D-76021 Karlsruhe, Germany Present address: Boehringer-Ingelheim RCV and Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
Jürgen
J
Moll
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany Present address: Georg-August-University Göttingen, Dept. of Neuropathology, Robert-Koch-Strasse 40, D-37075 Göttingen, Germany.
Anne
A
Winkler
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany INSERM, Oncogenèse et Progression Tumorale, Université Claude Bernard Lyon I, 28 rue Laënnec, 69373 Lyon, France.
Lucien
L
Frappart
Collège de France, 11 place Marcelin Berthelot, 75231 Paris, France.
Stéphane
S
Brunet
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.
Jana
J
Hamann
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.
Torsten
T
Kroll
Collège de France, 11 place Marcelin Berthelot, 75231 Paris, France.
Marie-Hélène
MH
Verlhac
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany Leibniz Research Institute for Environmental Medicine (IUF), 40021 Düsseldorf, Germany.
Heike
H
Heuer
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany ploubidou@fli-leibniz.de herrlich@fli-leibniz.de.
Peter
P
Herrlich
Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany ploubidou@fli-leibniz.de herrlich@fli-leibniz.de.
Aspasia
A
Ploubidou
Centrosome; Folliculogenesis; Gametogenesis; Hypofertility; Oriented mitosis; RHAMM; Spindle