Sexual dimorphism in developmental programming caused by CSF2

项目总结 植入前胚胎的发育程序会因其微环境的变化而改变。 由此产生的发育变化可能会产生长期影响，并延伸到出生后的生活中。不适当 母亲和胚胎之间的信号传递可能会导致更多的妊娠损失和长期的健康变化。 对发展规划的研究可导致消除相关的不利后果 通过试管受精，产生了新的方法来全面改善人类健康和动物生产。一 着床前期发育规划的特点是性别二态 成体表型的修饰。胚胎对微环境变化反应的性别差异 可能部分是通过胚胎对母体调节信号的性别特异性反应来调节的。一 参与这一现象的分子是集落刺激因子2(CSF2)。在牛身上，桑拿液和桑拿液的治疗 带有CSF2的囊胚期胚胎在怀孕后期(第15天)改变了胚胎特征 在特定性别的方式下，至少在雌性后代中，导致小牛在 生命的第一年。长期目标是了解胚胎的微环境如何与 性来塑造发育计划。当前提案的总体目标是：1)阐明 CSF2引起雄性和雌性胚胎差异编程作用的机制和2) 描述CSF2对体外和体内植入前胚胎的影响 随后的胚胎和出生后的表型。据推测，对CSF2的性别依赖性反应 依赖于CSF2和CsF2对DNA甲基化重塑的男女胚胎的差异 DNA甲基化的这些变化会对发育程序产生长期影响 对出生后表型的影响。有三个具体目标。对于目标1，将测试是否 雌雄着床前胚胎在第15天对CSF2编程行为的差异 胚胎依赖于DNA甲基化。对于目标2，CSF2对胚胎发育的重要性 在体内的评估将通过测试敲除CSF2受体对胚胎延伸的影响来进行， 男性和女性胚胎的基因表达和DNA甲基化。目标3将专注于确定 将植入前女性胚胎暴露于CSF2程序开发以改变出生后表型 一种提高奶牛生产力的方式。通过这些目标，我们将阐明重塑的重要性 CSF2的性别相关作用的甲基组(目标1)，并确定CSF2的作用是否发生 不仅在体外，而且在子宫内发育的胚胎也是如此(目标2)。最后，目标3的实验代表了 利用发展规划提高食用动物生产力的首次尝试 分子调控着床前期的发育。 。

PROJECT SUMMARY The developmental program of the preimplantation embryo is modified by alterations in its microenvironment. The resultant change in development can have long-acting effects that extend into postnatal life. Inappropriate signaling between mother and embryo can lead to increased pregnancy loss and long-term changes in health. Research on developmental programming could lead to elimination of adverse outcomes associated with IVF and result in new approaches to improve human health and animal production generally. One characteristic of developmental programming during the preimplantation period is sexual dimorphism in the modification in adult phenotype. Sex differences in embryonic responses to changes in the microenvironment are likely mediated in part by sex-specific responses of the embryo to maternal regulatory signals. One molecule involved in this phenomenon is colony stimulating factor 2 (CSF2). In cattle, treatment of morula and blastocyst stage embryos with CSF2 changed embryonic characteristics at a later point in pregnancy (Day 15) in a sex-specific manner and, at least in female offspring, resulted in calves with increased growth rates in the first year of life. The long-term goal is to understand how the microenvironment of the embryo interacts with sex to shape the developmental program. The overall objectives of the current proposal are to 1) elucidate mechanisms by which CSF2 causes differential programming actions on male and female embryos and 2) characterize the consequences of actions of CSF2 on the preimplantation embryo in vitro and in vivo for subsequent embryonic and postnatal phenotype. It is hypothesized that sex-dependent responses to CSF2 depend upon differences between male and female embryos in remodeling of DNA methylation by CSF2 and that these changes in DNA methylation result in long-acting effects on the developmental program that have consequences for postnatal phenotype. There are three specific aims. For Aim 1, it will be tested whether differences between male and female preimplantation embryos in programming actions of CSF2 on the Day 15 embryo are dependent upon DNA methylation. For Aim 2, the importance of CSF2 for embryonic development in vivo will be evaluated by testing consequences of knocking out the CSF2 receptor for embryo elongation, gene expression and DNA methylation in male and female embryos. Aim 3 will focus on ascertaining whether exposure of the preimplantation female embryo to CSF2 programs development to alter postnatal phenotype in a manner that improves dairy cow productivity. Through these aims, we will elucidate importance of remodeling of the methylome for sex-dependent actions of CSF2 (Aims 1) and ascertain whether actions of CSF2 occur not only in vitro but also for embryos developing in utero (Aim 2). Finally, the experiment for Aim 3 represents the first attempt to enhance productivity of a food animal through use of a developmental programming molecule to manipulate development in the preimplantation period. .