Gene Regulatory Networks for Mullerian Duct Regression

苗勒氏管回归的基因调控网络

基本信息

批准号：
10311623
负责人：
Malcolm Mauriece Moses
金额：
$ 3.35万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311623
关键词：
ATAC-seq Adult Bacterial Artificial Chromosomes Binding Biological Assay Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Computer Analysis Data Elements Embryonic Development Enhancers Epididymis Epigenetic Process Female Genetic Genetic Enhancer Element Genetic Transcription Genomics Human In Vitro Knockout Mice Knowledge LacZ Genes Mammalian Oviducts Mammals Maps Mediating Mesenchymal Mesenchyme Mullerian-inhibiting substance receptor Mus Organ Ovary Patients Regulation Regulator Genes Reporter Seminal Vesicles Sex Differentiation Sexual Development Signal Pathway Structure of mesonephric duct Structure of paramesonephric duct Syndrome Testis Tissues Transcriptional Regulation Transgenic Mice Transgenic Organisms Uterus Vagina Vas deferens structure candidate identification experimental study fetal genome analysis genomic data granulosa cell in vivo insight interest leydig interstitial cell male mullerian-inhibiting hormone mutant postnatal progenitor receptor reproductive tract sertoli cell

项目摘要

Mammals, including humans, develop progenitor tissues for both male and female reproductive tract organs before fully differentiating into a male or female. The progenitor tissue for the male reproductive tract is known as the Wolffian duct, and the progenitor tissue for the female reproductive tract is the Müllerian duct. The Wolffian duct further differentiates into the vas deferens, epididymis, and seminal vesicle, while the Müllerian duct differentiates into the oviduct, uterus and upper vagina. An essential step in sex differentiation for males is the regression of the Müllerian ducts. This regression initiates with anti-Müllerian hormone (Amh) transcription in the fetal testes about 12.5 days into embryonic development (E12.5) and approaches completion at E17.5. It is known that Müllerian duct regression requires the binding of AMH, after it is released from the fetal testes, to its primary receptor AMHR2 in the Müllerian duct mesenchyme. This is evidenced by experiments in which male knockout mice that did not express either Amh or Amhr2 did not undergo Müllerian duct regression. Thus, Amh/Amhr2 are essential for male sex differentiation. Male patients without functional AMH or AMHR2 have a uterus, a condition known as Persistent Müllerian Duct Syndrome (PMDS), a difference in sex development (DSD). Amhr2 is expressed in the Müllerian duct mesenchyme, Sertoli, Leydig, and postnatal granulosa cells. Transcriptional regulation of Amhr2 has been studied in Sertoli, Leydig, and granulosa cells in vitro. We have described a gene regulatory network (GRN) for Müllerian duct regression. Our GRN for Müllerian duct regression has illuminated the need to identify the Müllerian duct mesenchyme specific transcriptional enhancer for Amhr2. This proposal uses in vivo transgenic mouse assays and ATAC-seq open chromatin assessments in Müllerian duct mesenchyme cells to identify the cis-elements required for Amhr2 transcription for Müllerian duct regression. This knowledge should inform the GRN for Müllerian duct regression and may provide new insights into the genesis of human DSDs.

包括人类在内的哺乳动物为雄性和女性生殖道器官开发祖细胞组织，然后完全区分男性或女性。雄性生殖道的祖细胞组织称为沃尔夫·管道，女性生殖道的祖细胞组织是穆勒风管。沃尔夫（Wolffian）的管道进一步区分了VAS延迟，附生膜和半韦斯特（Sepidymis），而穆勒（Müllerian）管道则分化为输卵管，子宫和上阴道。男性性别差异的重要一步是穆勒风管的回归。这种回归在胎儿测试中以抗肿瘤的转录（AMH）转录启动，大约12.5天（E12.5）（E12.5），接近E17.5。众所周知，Müllerian管道回归需要AMH从胎儿试验释放到其在Müllerian管间隙中的主要受体AMHR2之后的结合。实验证明了这一点是，未表达AMH或AMHR2的雄性敲除小鼠未在Müllerian管道回归下。那是AMH/AMHR2对于男性性别差异至关重要。没有功能性AMH或AMHR2的男性患者具有子宫，这种病被称为持续的müllerian管道综合征（PMDS），性别发展差异（DSD）。 AMHR2在Müllerian管间质，Sertoli，Leydig和产后颗粒细胞中表达。 AMHR2的转录调控已在体外在Sertoli，Leydig和颗粒细胞中进行了研究。我们已经描述了一个用于Müllerian管道回归的基因调节网络（GRN）。我们为Müllerian管道回归的GRN阐明了识别AMHR2的Müllerian管间质特异性转录增强子的需求。该提案使用Müllerian管间充质细胞中的体内转基因小鼠评估和ATAC-SEQ开放染色质评估来鉴定Müllr2转录所需的顺式元素。这些知识应该为穆勒的导管回归提供信息，并可能为人类DSD的起源提供新的见解。