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RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.

Li H, Moll J, Winkler A, Frappart L, Brunet S, Hamann J, Kroll T, Verlhac MH, Heuer H, Herrlich P, Ploubidou A - Biol Open (2015)

Bottom Line: This resulted in folliculogenesis defects and female hypofertility, although HA-induced signalling was not affected.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.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.

No MeSH data available.


The RHAMM centrosome-targeting domain is required for adult ovarian folliculogenesis.Visualization (A–F) and quantification (G,H) of ovarian follicles in adult mice reveals a severe folliculogenesis defect in hmmrm/m mutants. (A–F) Hematoxylin- and eosin-stained representative sections of ovaries from hmmr+/+ (A) and hmmrm/m (D) females demonstrate depletion of the hmmrm/m ovary of follicles. However, the few follicles formed in hmmrm/m ovaries (E,F) exhibit no morphological defects as compared to controls (B,C). Boxes in A and D indicate the magnified areas in B,C and E,F, respectively. (G) Quantification of primary follicles (e.g. B,E) in ovaries of 10-week-old mice, reveals a severe folliculogenesis defect in hmmrm/m mutants, which contain up to 5-fold decreased number of these follicles when compared to their wild type counterparts. (H) The defective folliculogenesis in RHAMM mutants is further demonstrated by the significant reduction of both immature (primary, secondary) and mature follicles (antral, preovulatory) in hmmrm/m ovaries, in 10-week-old as well as in 25-week-old mice. In G,H (10-week-olds), hmmr+/+ n = 11 and hmmrm/m n = 4; in H (24-week-olds), hmmr+/+ n = 4 and hmmrm/m n = 4. Data presented as mean±s.d.; ***p<0.001. Scale bars: 200 µm (A,D); 20 µm (B,C,E,F).
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f04: The RHAMM centrosome-targeting domain is required for adult ovarian folliculogenesis.Visualization (A–F) and quantification (G,H) of ovarian follicles in adult mice reveals a severe folliculogenesis defect in hmmrm/m mutants. (A–F) Hematoxylin- and eosin-stained representative sections of ovaries from hmmr+/+ (A) and hmmrm/m (D) females demonstrate depletion of the hmmrm/m ovary of follicles. However, the few follicles formed in hmmrm/m ovaries (E,F) exhibit no morphological defects as compared to controls (B,C). Boxes in A and D indicate the magnified areas in B,C and E,F, respectively. (G) Quantification of primary follicles (e.g. B,E) in ovaries of 10-week-old mice, reveals a severe folliculogenesis defect in hmmrm/m mutants, which contain up to 5-fold decreased number of these follicles when compared to their wild type counterparts. (H) The defective folliculogenesis in RHAMM mutants is further demonstrated by the significant reduction of both immature (primary, secondary) and mature follicles (antral, preovulatory) in hmmrm/m ovaries, in 10-week-old as well as in 25-week-old mice. In G,H (10-week-olds), hmmr+/+ n = 11 and hmmrm/m n = 4; in H (24-week-olds), hmmr+/+ n = 4 and hmmrm/m n = 4. Data presented as mean±s.d.; ***p<0.001. Scale bars: 200 µm (A,D); 20 µm (B,C,E,F).

Mentions: In ovaries of 10-week-old hmmrm/m mice, the number of primary follicles was decreased 5-fold as compared to the controls (Fig. 4G) indicating a defect in the transition from primordial to primary follicles. Moreover, in hmmr+/+ ovaries, follicles of various maturation stages were present, indicating ongoing folliculogenesis (Fig. 4A). In contrast, mostly degenerative (“atretic”) follicles, with increased interstitial tissue, can be seen in a representative section of an hmmrm/m ovary (Fig. 4D). Quantification of the ovarian follicles in adult animals, using (one in every five) 4 µm semi-serial sections of complete ovaries (Canning et al., 2003; Tilly, 2003) from 10- and 25-week-old females, confirmed these observations (Fig. 4H). The number of both immature (primary and secondary) and mature follicles (antral and preovulatory) was very significantly decreased in hmmrm/m ovaries, compared to their hmmr+/+ counterparts, at both age time-points analyzed. As mice got older, the number of immature and mature follicles increased in the hmmr+/+ ovaries while decreasing (up to 100-fold) in hmmrm/m ones (Fig. 4H).


RHAMM deficiency disrupts folliculogenesis resulting in female hypofertility.

Li H, Moll J, Winkler A, Frappart L, Brunet S, Hamann J, Kroll T, Verlhac MH, Heuer H, Herrlich P, Ploubidou A - Biol Open (2015)

The RHAMM centrosome-targeting domain is required for adult ovarian folliculogenesis.Visualization (A–F) and quantification (G,H) of ovarian follicles in adult mice reveals a severe folliculogenesis defect in hmmrm/m mutants. (A–F) Hematoxylin- and eosin-stained representative sections of ovaries from hmmr+/+ (A) and hmmrm/m (D) females demonstrate depletion of the hmmrm/m ovary of follicles. However, the few follicles formed in hmmrm/m ovaries (E,F) exhibit no morphological defects as compared to controls (B,C). Boxes in A and D indicate the magnified areas in B,C and E,F, respectively. (G) Quantification of primary follicles (e.g. B,E) in ovaries of 10-week-old mice, reveals a severe folliculogenesis defect in hmmrm/m mutants, which contain up to 5-fold decreased number of these follicles when compared to their wild type counterparts. (H) The defective folliculogenesis in RHAMM mutants is further demonstrated by the significant reduction of both immature (primary, secondary) and mature follicles (antral, preovulatory) in hmmrm/m ovaries, in 10-week-old as well as in 25-week-old mice. In G,H (10-week-olds), hmmr+/+ n = 11 and hmmrm/m n = 4; in H (24-week-olds), hmmr+/+ n = 4 and hmmrm/m n = 4. Data presented as mean±s.d.; ***p<0.001. Scale bars: 200 µm (A,D); 20 µm (B,C,E,F).
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f04: The RHAMM centrosome-targeting domain is required for adult ovarian folliculogenesis.Visualization (A–F) and quantification (G,H) of ovarian follicles in adult mice reveals a severe folliculogenesis defect in hmmrm/m mutants. (A–F) Hematoxylin- and eosin-stained representative sections of ovaries from hmmr+/+ (A) and hmmrm/m (D) females demonstrate depletion of the hmmrm/m ovary of follicles. However, the few follicles formed in hmmrm/m ovaries (E,F) exhibit no morphological defects as compared to controls (B,C). Boxes in A and D indicate the magnified areas in B,C and E,F, respectively. (G) Quantification of primary follicles (e.g. B,E) in ovaries of 10-week-old mice, reveals a severe folliculogenesis defect in hmmrm/m mutants, which contain up to 5-fold decreased number of these follicles when compared to their wild type counterparts. (H) The defective folliculogenesis in RHAMM mutants is further demonstrated by the significant reduction of both immature (primary, secondary) and mature follicles (antral, preovulatory) in hmmrm/m ovaries, in 10-week-old as well as in 25-week-old mice. In G,H (10-week-olds), hmmr+/+ n = 11 and hmmrm/m n = 4; in H (24-week-olds), hmmr+/+ n = 4 and hmmrm/m n = 4. Data presented as mean±s.d.; ***p<0.001. Scale bars: 200 µm (A,D); 20 µm (B,C,E,F).
Mentions: In ovaries of 10-week-old hmmrm/m mice, the number of primary follicles was decreased 5-fold as compared to the controls (Fig. 4G) indicating a defect in the transition from primordial to primary follicles. Moreover, in hmmr+/+ ovaries, follicles of various maturation stages were present, indicating ongoing folliculogenesis (Fig. 4A). In contrast, mostly degenerative (“atretic”) follicles, with increased interstitial tissue, can be seen in a representative section of an hmmrm/m ovary (Fig. 4D). Quantification of the ovarian follicles in adult animals, using (one in every five) 4 µm semi-serial sections of complete ovaries (Canning et al., 2003; Tilly, 2003) from 10- and 25-week-old females, confirmed these observations (Fig. 4H). The number of both immature (primary and secondary) and mature follicles (antral and preovulatory) was very significantly decreased in hmmrm/m ovaries, compared to their hmmr+/+ counterparts, at both age time-points analyzed. As mice got older, the number of immature and mature follicles increased in the hmmr+/+ ovaries while decreasing (up to 100-fold) in hmmrm/m ones (Fig. 4H).

Bottom Line: This resulted in folliculogenesis defects and female hypofertility, although HA-induced signalling was not affected.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.

View Article: PubMed Central - PubMed

Affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute, Beutenbergstrasse 11, D-07745 Jena, Germany.

No MeSH data available.