Woodlands sheep have a putative genetic mutation (FecX2(W)) that increases ovulation rate. At present, the identity of FecX2(W) is unknown. The trait does not appear to be due to the previously described mutations in bone morphogenetic protein 15 (BMP15), growth differentiation factor 9 (GDF9), or bone morphogenetic protein receptor type 1B (BMPR1B) that affect ovulation rate in sheep. Potentially, FecX2(W) could be an unidentified genetic mutation in BMP15 or in the closely related GDF9, which interacts with BMP15 to control ovarian function. Alternatively, FecX2(W) may affect ovulation rate by changing the expression patterns in the molecular pathways activated by genes known to regulate ovulation rate. The objectives of these experiments were to sequence the complete coding region of the BMP15 and GDF9 genes, determine the patterns of expression of mRNAs encoding GDF9, BMP15, TGFBR1, BMPR1B, and BMPR2 during follicular development, and characterize the follicular populations in ewes heterozygous for the Woodlands mutation and their wild-type contemporaries. No differences in the coding sequences of BMP15 or GDF9 genes were identified that were associated with enhanced ovulation rate. The expression patterns of GDF9 and BMPR2 mRNAs were not different between genotypes. However, expression of BMP15 mRNA was less in oocytes of FecX2(W) ewes in large preantral and antral follicles. Expression of ALK5 mRNA was significantly higher in the oocytes of FecX2(W) ewes, whereas expression of BMPR1B was decreased in both oocytes and granulosa cells of FecX2(W) ewes. FecX2(W) ewes also had increased numbers of antral follicles <1 mm in diameter. These follicles were smaller in average diameter, with the oocytes also being of a smaller mean diameter. Given that a mutation in BMP15 or BMPR1B results in increased ovulation rates in sheep, the differences in expression levels of BMP15 and BMPR1B may play a role in the increase in ovulation rate observed in Woodlands ewes with the FecX2(W) mutation.
Attainment of puberty is a key developmental event influenced by genetic and environmental factors. In examining age at attainment of puberty, we observed closely related rams from the Davisdale line whose daughters differed in age at which they attained puberty. A candidate gene approach was used to identify mutations that may underlie these observed differences. Four rams with divergent phenotypes for their daughter's age at onset of puberty were selected for whole-genome sequencing. The coding regions of genes with known roles in regulating reproductive function were searched for single-nucleotide polymorphisms (SNPs) that altered the amino acid sequence of the protein. Of interest were three SNPs in the leptin receptor gene (LEPR). A Sequenom assay was developed to determine the genotype of these SNPs in daughters of 17 sons of a founding sire. A higher percentage of ewe lambs homozygous for the LEPR mutations failed to undergo puberty before 1 yr of age, and those that did undergo puberty during the first breeding season on average were approximately 17 days older than homozygous wild-type ewes. Heterozygous ewes were intermediate for both measurements. Given the predicted change in protein function produced by the mutation in LEPR and the strong associations between the genotype and onset of puberty phenotypes, we propose that this mutation in LEPR underlies the observed difference in age at onset of puberty in the Davisdale line. Furthermore, these animals will likely provide a useful model to better understand the role of leptin in the regulation of puberty.
We hypothesised that cocaine- and amphetamine-regulated transcript () would be differentially expressed in ewes with differing ovulation rates. Expression of mRNA for , as well as, , and was determined in antral follicles ≥1 mm in diameter collected during the follicular phase in ewes heterozygous for the Booroola and Inverdale genes (I+B+; average ovulation rate 4) and ++ contemporaries (++; average ovulation rate 1.8). In ++ ewes ( = 6), was expressed in small follicles (1 to<3 mm diameter), where 18.8 ± 2.5% follicles expressed CART peptide was also detected in follicular fluid of some follicles of ++ ewes. In I+B+ ewes, 5/6 ewes did not have any follicles that expressed, and no CART peptide was detected in any follicle examined. Expression pattern of differed between I+B+ and ++ ewes with an increased percentage of small and medium follicles (3 to<4.5 mm diameter) but decreased percentage of large follicles (≥4.5 mm diameter) expressing in the I+B+ ewes. Many of the large follicles from the I+B+ ewes appeared non-functional and expression of, , and was less than that observed in ++ ewes. Expression of and was not different between groups in small and medium follicles, but expression was approximately double in I+B+ ewes compared to that in ++ ewes. Thus, ewes with high ovulation rates had a distinct pattern of expression of mRNA and protein compared to ewes with normal ovulation rates, providing evidence for CART being important in the regulation of ovulation rate.
Vesicoureteric reflux (VUR) is a common childhood condition characterised by regurgitation of urine from the bladder to the kidney. It is the commonest cause of end stage renal failure in children and an important cause in adults. Primary VUR is often familial, suggesting that genetic factors play an important role in its aetiology. Recently, VUR was observed as part of a syndrome, involving optic nerve colobomas and renal anomalies, caused by mutations of the PAX2 gene. PAX2 is a member of the paired box family of genes and is expressed in the ureteric bud and differentiating nephrogenic mesenchyme of the developing kidney. PAX2 has been shown to play a critical role in the development of both the kidney and the ureter. The occurrence of VUR in one family with the PAX2 mutation, and the expression pattern of PAX2 in developing ureteric bud, strongly suggested that PAX2 could be the cause of primary familial VUR. Single strand conformational polymorphism (SSCP) analysis of 23 affected subjects in eight families with primary familial VUR showed no alterations in exons 2-5 of the PAX2 gene. In addition, a polymorphic dinucleotide repeat marker located within the PAX2 gene segregated independently of the disease trait in one large family who primarily had VUR or reflux nephropathy. These results suggest that PAX2 is not a major cause of primary familial reflux.
Sheep lines with mutations in single genes that have major effects on ovulation rate have been very useful in gaining a better understanding of pathways important in controlling follicular development and ovulation rate. To date however, all known mutations are in the transforming growth factor beta (TGFB) superfamily. Ovulation rates were measured in 720 progeny of 20 rams that were descendants of a single prolific ewe. Evaluation of ovulation rates of daughters of closely related sires suggests the presence of a segregating major gene Fecundity Davisdale (FECD) that increases ovulation rate between 0.4 and 0.8 in heterozygous daughters. Key features of mutations in genes of the TGFB superfamily pathway, such as synergistic interactions with other family members, infertility in homozygous carriers, and increased responsiveness to exogenous gonadotropins, were not observed in this line; thus, the mutation does not appear to be acting in the TGFB pathway. Hence, there is likely a novel mutation being carried in this line of sheep that alters ovulation rate. Future identification of the causative mutation may provide new insights into regulation of follicular development and ovulation rate.
The objective of this study was to determine whether differences in mRNA levels of key pituitary genes that regulate GH production, pituitary development, and growth were present and/or associated with divergent body composition phenotypes observed between sheep from genetically divergent lean and fat selection lines. Real-time PCR transcription profiles for pituitary specific transcription factor 1, prophet of pit1, GH, GH receptor, GH secretagogue receptor, GHRH receptor, leptin receptor, and somatostatin receptors 1 and 2 were determined in pituitary tissue. There was a difference in the amount of both GH (P < 0.001) and GH secretagogue receptor (P < 0.001) mRNA between the selection lines (5 females and 5 males per line; 20 wk of age); the lean line had greater abundance than the fat line, irrespective of which endogenous control gene was used. The results obtained for GHRH receptor were equivocal but suggestive; there were greater GHRH receptor mRNA levels (P < 0.001) in the lean line using beta-2-microglobulin as the endogenous control but not when hypoxanthine phosphoribosyltransferase and glyceraldehyde-3-phosphate dehydrogenase were used. No difference in pituitary specific transcription factor 1, prophet of pit1, GH receptor, leptin receptor, or somatostatin receptors 1 and 2 mRNA concentration was observed between the lines. The greater abundance of GH mRNA in the pituitary somatotropes from genetically lean animals appears to be associated with increased levels of GH secretagogue receptor mRNA and possibly GHRH receptor mRNA. This suggests that the difference in GH secretion between the lines may be due to differences in the afferent signals, such as ghrelin and/or GHRH, arising from the hypothalamus, or as a result of differential pituitary sensitivity to these hormones.
The aim of this study was to determine if single nucleotide polymorphisms (SNPs) in the leptin receptor (LEPR) gene associated with delayed onset of puberty are associated with changes in other reproductive traits in adult ewes. The ovulation rate of ewes homozygous for the SNPs was ~15% lower (PPLEPR SNPs than their wild-type or heterozygous contemporaries. Partial failure of multiple ovulations was also increased (PLEPR had on average 0.2 fewer lambs at mid-pregnancy and at birth compared with the wild-type or heterozygous ewes (PLEPR were strongly associated with poorer reproductive performance in Davisdale ewes, which is likely to be linked to both a reduced number of ova available for fertilisation and an increased number of ewes failing to become pregnant. Increased partial failure of multiple ovulations in ewes with high ovulation rates (i.e. 3 or greater) may also contribute to the poor reproductive performance.
Regulation of the growth and maturation of the ovarian follicle is critical for normal reproductive function. Alterations in this growth can lead to pathological conditions, such as cystic follicles, reduced oocyte quality, or an abnormal endocrine environment leading to poor fertility. Alterations in follicular growth also influence the number of follicles ovulating and thus can change litter size. Both endocrine factors, such as follicle stimulating hormone and luteinizing hormone, as well as local factors, are known to regulate follicular growth and development. This review will focus on the role of local factors in regulation of ovarian follicular growth in ruminants, with a focus on members of the transforming growth factor superfamily. The potential role of these factors in regulating proliferation, apoptosis, steroidogenesis and responsiveness to gonadotrophins will be considered.
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