Genetic mutations influencing ovulation rate in sheep

2001 ◽  
Vol 13 (8) ◽  
pp. 549 ◽  
Author(s):  
K. P. McNatty ◽  
J. L. Juengel ◽  
T. Wilson ◽  
S. M. Galloway ◽  
G. H. Davis
Keyword(s):  
Growth Factor ◽  
Point Mutation ◽  
Transforming Growth Factor ◽  
Somatic Cells ◽  
Follicular Development ◽  
Experimental Models ◽  
Ovulation Rate ◽  
Corpora Lutea ◽  
Coding Region ◽  
Primary Stage

Ovulation rate in mammals is determined by a complex exchange of endocrine signals between the pituitary gland and the ovary, and by paracrine signals within ovarian follicles between the oocyte and its adjacent somatic cells. One approach to identifying factors regulating ovulation rate is to find mutations that influence the target phenotype and, in this context, sheep are proving to be remarkable experimental models. Recently, in three sheep families, namely Inverdale, Hanna and Booroola, the inherited mutation was mapped to a specific region of the sheep X chromosome (Inverdale, Hanna) or sheep chromosome 6 (Booroola) and in each, a point mutation was identified in genes from the bone morphogenetic protein (BMP) relatives of the transforming growth factor ‚ superfamily or their receptors. In Inverdale (I) and Hanna (H) sheep, separate point mutations were identified in the BMP15 gene corresponding to sites in the mature peptide coding region of the BMP15 growth factor (also known as growth differentiation factor 9B; GDF9B). Expression of the BMP15 gene was located exclusively in oocytes from the primary stage of follicular growth. There is a complete block of normal follicular development in females carrying two copies of the Inverdale mutation (II), two copies of the Hanna mutation (HH), or one copy of each mutation (HI). Increased ovulation rates are found in females with only one copy of either mutation (I+ or H+). In Booroola sheep, a point mutation was identified in the highly conserved intracellular serine threonine kinase signalling domain of the BMP-1B receptor. Within the ovary, this gene is expressed in oocytes in primordial and pre-antral follicles and in granulosa cells from the primary stage of growth as well as in corpora lutea. The effect of the Booroola mutation is additive for ovulation rate: animals with one copy of the mutation have an ovulation rate of 3 or 4, whereas those with two copies have an ovulation rate of between 5 and 14. Physiological studies of the above mutations demonstrate that the oocyte plays an active role with respect to its adjacent somatic cells during follicular development and support the hypothesis that the oocyte has a significant influence on the number of follicles that proceed to ovulation.

scholarly journals Active immunization against the proregions of GDF9 or BMP15 alters ovulation rate and litter size in mice

Reproduction ◽  
2012 ◽  
Vol 143 (2) ◽  
pp. 195-201 ◽  
Author(s):  
C Joy McIntosh ◽  
Steve Lawrence ◽  
Peter Smith ◽  
Jennifer L Juengel ◽  
Kenneth P McNatty
Keyword(s):  
Litter Size ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cross Reactivity ◽  
Full Length ◽  
Ovulation Rate ◽  
Corpora Lutea ◽  
Immunization Group

The transforming growth factor β (TGFB) superfamily proteins bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9), are essential for mammalian fertility. Recent in vitro evidence suggests that the proregions of mouse BMP15 and GDF9 interact with their mature proteins after secretion. In this study, we have actively immunized mice against these proregions to test the potential in vivo roles on fertility. Mice were immunized with either N- or C-terminus proregion peptides of BMP15 or GDF9, or a full-length GDF9 proregion protein, each conjugated to keyhole limpet hemocyanin (KLH). For each immunization group, ovaries were collected from ten mice for histology after immunization, while a further 20 mice were allowed to breed and litter sizes were counted. To link the ovulation and fertility data of these two experimental end points, mice were joined during the time period identified by histology as being the ovulatory period resulting in to the corpora lutea (CL) counted. Antibody titers in sera increased throughout the study period, with no cross-reactivity observed between BMP15 and GDF9 sera and antigens. Compared with KLH controls, mice immunized with the N-terminus BMP15 proregion peptide had ovaries with fewer CL (P<0.05) and produced smaller litters (P<0.05). In contrast, mice immunized with the full-length GDF9 proregion not only had more CL (P<0.01) but also had significantly smaller litter sizes (P<0.01). None of the treatments affected the number of antral follicles per ovary. These findings are consistent with the hypothesis that the proregions of BMP15 and GDF9, after secretion by the oocyte, have physiologically important roles in regulating ovulation rate and litter size in mice.

scholarly journals Gene expression of growth factor BMP15, GDF9, FGF2 and their receptors in bovine follicular cells

2018 ◽  
pp. 6778-6787 ◽  
Author(s):  
Pablo S Reineri ◽  
María S. Coria ◽  
María G. Barrionuevo ◽  
Olegario Hernández ◽  
Santiago Callejas ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Follicular Development ◽  
Fibroblast Growth ◽  
Rt Pcr ◽  
Follicular Cells

Introduction. Growth and follicular maturation involve transformations of various components of the follicle, such as the oocyte, granulosa and techa cells. Several growth factors, including differentiation growth factor 9 (GDF9), bone morphogenic protein 15 (BMP15) and basic fibroblast growth factor (FGF2) are important for follicular development and oocyte maturation, by its ability to increase the proliferation of granulosa, techa cells and the ovarian stroma. Objetive. Evaluate mRNA expression of GDF9, BMP15, FGF2 and their main receptors, transforming growth factor beta receptor 1 (TGFβ-R1), bone morphogenetic protein receptor, type IB (BMPR-IB) and fibroblast growth factor receptor 2 (FGFR2) in bovine follicular cells. Materials and methods. Total RNA was isolated from pooled samples of oocytes (OOs), cumulus cells (CCs) of cumulus oocyte complexes (COCs) and follicular cell pellets (PCs) of 70 ovaries obtained from 96 beef heifers, collected at a local abattoir. The expression pattern of growth factors and their receptors in follicular bovine cells was evaluated by reverse transcriptase polymerase chain reaction (RT-PCR). Results. The mRNA transcripts encoding GDF9, BMP15, FGF2, TGFβ-R1, BMPR-IB and FGFR2 genes were detected, by RT-PCR, in all studied cells. This is the first time that the expression of TGFβ-R1 and BMPR-IB receptors is reported in bovine oocytes. Conclusions. The presence of growth factors and receptor transcripts in the studied cells indicate that these factors could act as paracrine and autocrine regulators of folliculogenesis.

Effect of active immunization of heifers against inhibin on plasma FSH concentrations, ovarian follicular development and ovulation rate

1992 ◽  
Vol 134 (1) ◽  
pp. 11-18 ◽  
Author(s):  
R. G. Glencross ◽  
E. C. L. Bleach ◽  
B. J. McLeod ◽  
A. J. Beard ◽  
P. G. Knight
Keyword(s):  
Synthetic Peptide ◽  
Ovarian Function ◽  
Statistical Significance ◽  
Follicular Development ◽  
Ovarian Response ◽  
Active Immunization ◽  
Ovulation Rate ◽  
Corpora Lutea ◽  
Α Subunit ◽  
Ovarian Follicular Development

ABSTRACT To study the effects of immunoneutralization of endogenous inhibin on gonadotrophin secretion and ovarian function, prepubertal heifers (n = 6) were actively immunized against a synthetic peptide replica of the N-terminal sequence of bovine inhibin α subunit bIα(1–29)Tyr30) coupled to ovalbumin. In contrast to ovalbumin-immunized controls (n=6), bIα(1–29)Tyr30-immunized heifers had detectable inhibin antibody titres (% binding to 125I-labelled bovine inhibin at 1:2000 dilution of plasma) of 17 ± 3% (s.e.m.) at puberty, rising to 31 ± 5% by the end of the study period 7 months later. Neither age (immunized: 295 ± 8 days; controls: 300 ± 5 days) nor body weight (immunized: 254 ± 13 kg; controls 251 ± 9 kg) at onset of puberty differed between groups. Although the difference did not reach statistical significance, mean plasma FSH concentrations recorded in inhibin-immunized heifers remained 35–40% higher than in controls throughout the 12-week period leading up to puberty (P = 0·14) and during nine successive oestrous cycles studied after puberty (P=0·10). Plasma LH concentrations did not differ between groups at any time during the study. Inhibin immunization had no effect on oestrous cycle length (immunized: 19·8±0·5 days; controls: 19·9±0·5 days). However, in comparison with controls, inhibinimmunized heifers had more medium sized (≥0·5 to <1 cm diameter) follicles during both the preovulatory (95%, P<0·001) and post-ovulatory (110%, P < 0·05 waves of follicular growth and more large (>1 cm diameter) follicles during the preovulatory wave (49%, P<0·05). In addition, the number of corpora lutea observed during the post-ovulatory phase of each cycle was significantly greater in the inhibin-immunized group (43%, P<0·01), as was the recorded incidence of cycles with multiple ovulations (19/56 in the inhibin-immunized group compared with 0/54 in controls; P<0·001). All six inhibinimmunized heifers had at least one cycle with multiple ovulation whereas none of the control heifers did so. These results support the conclusion that immunoneutralization of endogenous inhibin using a synthetic peptide-based vaccine can enhance ovarian follicular development and ovulation rate in heifers. Whether this ovarian response is dependent upon the expected increase in secretion of FSH remains to be established. Journal of Endocrinology (1992) 134, 11–18

scholarly journals Osteoprotegerin expression in liver is induced by IL-13 through TGF-β

2020 ◽  
Author(s):  
Adhyatmika Adhyatmika ◽  
Kurnia SS Putri ◽  
Emilia Gore ◽  
Keri Mangnus ◽  
Catharina Reker-Smit ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Tissue ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Experimental Models ◽  
Wild Type ◽  
3T3 Fibroblasts ◽  
Liver Slices ◽  
Deficient Mice

Backgrounds: Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elucidate which growth factors/interleukins associated with fibrosis induce OPG and through which pathways. Methods: Precision-cut liver slices of wild type and STAT6-deficient mice and 3T3 fibroblasts were used to investigate the effects of TGFβ, interleukin (IL) 13 (IL13), IL1β, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG. Results: In addition to TGFβ, only IL13 and not PDGF-BB or IL1β could induce OPG expression in 3T3 fibroblasts and liver slices. This IL13-dependent induction was not shown in liver slices of STAT6-deficient mice and when wild type slices were cotreated with TGFβ receptor 1 kinase inhibitor galunisertib, STAT6 inhibitor AS1517499, or AP1 inhibitor T5224. This suggests that the OPG-inducing effect of IL13 is mediated through IL13 receptor α1-activation and subsequent STAT6-dependent upregulation of IL13 receptor α2, which in turn activates AP1 and induces production of TGFβ and subsequent production of OPG. Conclusion: We have shown that IL13 induces OPG release by liver tissue through a TGFβ-dependent pathway involving both the α1 and the α2 receptor of IL13 and transcription factors STAT6 and AP1. OPG may therefore be a novel target for the treatment liver fibrosis as it is mechanistically linked to two important regulators of fibrosis in liver, namely IL13 and TGFβ1.

020. Oocyte signalling molecules and their effects on reproduction in ruminants

2005 ◽  
Vol 17 (9) ◽  
pp. 66
Author(s):  
K. P. McNatty
Keyword(s):  
Granulosa Cells ◽  
Point Mutations ◽  
Follicular Development ◽  
Ovis Aries ◽  
Ovulation Rate ◽  
Active Immunisation ◽  
Primary Stage ◽  
Signalling Molecules ◽  
Stage Of Development

Sheep (Ovis aries) are a highly diverse species with more than 900 different breeds that vary significantly in their physiological characteristics including ovulation rate and fecundity. From examination of inherited patterns of ovulation rate in sheep, several breeds have been identified with point mutations in two growth factor genes that are expressed in oocytes. Currently, five different point mutations have been identified in the BMP15 (GDF9b) gene and one in GDF9. Animals heterozygous for the GDF9 and/or the BMP15 mutations have higher ovulation rates (i.e. +0.6 to +5.0) than their wild-type contemporaries. In contrast, those homozygous for any of the aforementioned BMP15 or GDF9 mutations are sterile due to abnormal follicular development from the primary stage of growth. In bovine and ovine ovaries, GDF9 is expressed exclusively in oocytes throughout follicular growth from the primordial stage of development, whereas in sheep BMP15 is expressed exclusively in oocytes from the primary stage: no data for BMP15 are available for the cow. In vitro, ovine GDF9 (oGDF9) has no effect on 3H-thymidine incorporation by either bovine or ovine granulosa cells, whereas oBMP15 has modest (1.2 to 1.6-fold; P < 0.05) stimulatory effects. GDF9 or BMP15 alone inhibited progesterone production by bovine granulosa cells, whereas with ovine cells only GDF9 was inhibitory. The effects of GDF9 and BMP15 together were often cooperative and not always the same as those observed for each factor alone. Active immunisation of ewes with BMP15 and/or GDF9 peptides affected ovarian follicular development and ovulation rate. Depending on the GDF9 and/or BMP15 vaccine formulation, ovulation rate was either increased or suppressed. For example, immunisation of ewes with a BMP15 peptide in a water based adjuvant has led to a 25% increase in lambs born per ewe lambing. Collectively the evidence suggests that oocyte signalling molecules have profound effects on reproduction in mammals including rodents, humans and ruminants. Moreover, that in vivo manipulation of these oocyte signalling molecules provides a new approach to managing the fertility of ruminants.

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