How cumulus cell function is regulated and why

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1 How cumulus cell function is regulated and why Robert Gilchrist How cumulus cell function is regulated and why Gilchrist RB (211) Reprod. Fert. Dev. 23:23-31 Endocrine & paracrine signaling coordinate folliculogenesis & oogenesis FSH, LH

2 and : species-specific effects on ovulation rate and fecundity 1. Expression restricted to oocytes 2. Essential for follicular development & fertility Mouse Sheep -/- sterile sterile +/- fertile high fertility -/- sub-fertile sterile +/- fertile high fertility +/-+/- fertile super fertile from Ken McNatty, NZ (Dong et al 1996, Yan et al 21, Galloway et al 2, Hanrahan et al 24) / and human fertility remature Ovarian Failure: Mutations and sequence variations in and Di asquale et al (24), Dixit et al (26), Laissue et al (26) DZ Twinning: Rare variants in mothers of DZ twins Montgomery et al (24), almer et al (26) COS: Aberrant oocyte expression of Teixeira Filho FL et al (22) OHSS: olymorphisms in predispose to OHSS?? Morόn et al (26) rocessing of and rocessing Site ro region Mature most TGF- family members M M or M M from David Mottershead, Adelaide Lack the 4 th cysteine, so non-covalent homodimers. Heterodimer?? Only unprocessed promature proteins in follicular fluid. Detection: no reliable assays. oor quality antibodies

3 of relative bioavailability of and? from Ken McNatty, NZ Major differences in role of / between mono & poly-ovular species Multiple complex processes possible, incl.: o Relative expression levels of and (Crawford & McNatty 212) o Inactivation (latency) of or (Simpson et al 212) Species-specificity of : ratios Crawford JL & McNatty K (212) Mol. Cell. Endocr. 348: Species-specificity of : ratios 6 : ratio 4 2 mouse rat pig sheep cow deer

4 Species-specificity of : ratios Crawford JL & McNatty K (212) Mol. Cell. Endocr. 348: Activation of latent human Simpson CM et al (212) Endocr. 153: Activation of latent human Simpson CM et al (212) Endocr. 153:

5 Activation of latent human Simpson CM et al (212) Endocr. 153: Synergistic interactions between and / interactions: McNatty et al 25a,b Mol. Cell. Endocr. Edwards et al 28 Endocr. Reader et al 211 Reprod. and synergism: MGCs ine Incorporation d Change) 3 H-Thymidi (Fol x : < and/or (ng/ml) Mottershead DG et al (212) Mol. Hum. Reprod. 18:

6 and synergism: CCs 5 x : =.17 ne Incorporation Change) 3 H-Thymidin (Fold Mottershead DG et al (212) Mol. Hum. Reprod. 18: and synergism: activation of Smad2/3 but not Smad1/5/8 signalling Type II Type I Type II Type I ALK 4/5/7 ALK 2/3/6 Smad2/3 Smad1/5/8 Smad 3 Activation (Luciferase, Fold Change) TGF- 1 BM6 + x : =.5 Smad 1/5/8 Activation (Luciferase, Fold Change) x : TGF- 1 >.5 BM and/or (ng/ml) and/or (ng/ml) 7 Smad 3 Activation 3 H-Thymidine Incorporation (Luciferase, Fold Change) (Fold Change) SB SB (µm) SB Type II Smad2/3 Type I ALK 4/5/7 / SB SB (µm) Mottershead DG et al (212) Mol. Hum. Reprod. 18:

7 and synergism is specific dine Incorporation old Change) 3 H-Thymid (Fo Activin A Activin B TGF- 1 BM6 BM7 Mottershead DG et al (212) Mol. Hum. Reprod. 18: What is the mechanistic basis of / synergism? / from David Mottershead, Adelaide Consequenes of homodimeric vs heterodimeric signalling Guo and Wu (212) Cytokine and growth factor reviews. Epub

8 Unusual features of oocyte-secreted / that affect CC function and fecundity Lack the 4 th cysteine, so non-covalent homo- or hetero-dimers?? Substantial / synergism. Mechanism? and are expressed and function together should be considered a functional unit, however. Expression ratios of and mrna are tightly regulated within a species, but differ substantially between species is predominant in rodents, in non-rodents rodomain mature domain interactions have notable effects on activity, and there are major differences between species is latent in humans and maybe most mono-ovular species Regulation of interactions or relative bioactivities of / may be a fundamental determinant of oocyte quality, and mammalian ovulation rates and fecundity Acknowledgements Robinson Institute, RCRH, University of Adelaide, Australia David Mottershead Lesley Ritter Jeremy Thompson Victoria University of Wellington, NZ Ken McNatty rince Henry s Institute of Medical Research, Melbourne Craig Harrison, Courtney Simpson, eter Stanton, David Robertson Funding -NHMRC Australia: rogram, rogram & Development Grants. CDA Fellowship - Cook Medical thanks.from Adelaide

9 Treatment with OSFs during IVM improves development Bovine: Native OSFs,, improves embryo development and quality (Hussein T et al 26 Dev. Biol. 296: ) Murine: improves blastocyst quality and fetal survival (Yeo CX et al 28 Hum. Reprod. 23:67-73) Bovine: Native OSFs,, have different temporal effects on improved embryo development and quality (Hussein T et al 211 Reprod. Fertil. Dev. 23: ) Caprine: Native OSFs improve embryo development of COCs from small antral follicles only (Romaguera R et al 211 Therio. Ref ) orcine: Native OSFs improve embryo development of parthenotes (Gomez MNL 211 Zygote.ref) Bovine: Native OSFs increase %MII, Gpx1 and Star expression, prevent zona hardening and improve embryo development (Dey et al 212) Oocyte-Secreted Factors Regulate CCs and Oocyte Developmental Competence Gilchrist RB (211) Reprod. Fert. Dev. 23:23-31