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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：
10475644
负责人：
Malcolm Mauriece Moses
金额：
$ 2.99万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10475644
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 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 gene regulatory network 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.

哺乳动物，包括人类，在完全分化成雄性或雌性之前，发育出雄性和雌性生殖道器官的祖细胞组织。男性生殖道的祖组织称为沃尔夫管，女性生殖道的祖组织是苗勒管。沃尔夫管进一步分化为输精管、附睾和精囊，而苗勒管分化为输卵管、子宫和上阴道。男性性别分化的一个重要步骤是苗勒管的退化。这种退化始于胚胎发育约12.5天（E12.5）时胎儿睾丸中的抗苗勒管激素（Amh）转录，并在E17.5时接近完成。众所周知，苗勒管退行需要AMH从胎儿睾丸释放后与苗勒管间充质中的主要受体AMHR 2结合。这通过不表达Amh或Amhr 2的雄性敲除小鼠不经历苗勒管退化的实验来证明。因此，Amh/Amhr 2是男性性别分化所必需的。没有功能性AMH或AMHR 2的男性患者有子宫，这种情况称为持续性苗勒管综合征（PMDS），性别发育差异（DSD）。Amhr 2在苗勒管间充质、支持细胞、间质细胞和出生后的颗粒细胞中表达。Amhr 2的转录调控已在体外支持细胞、间质细胞和颗粒细胞中进行了研究。我们已经描述了苗勒管退化的基因调控网络（GRN）。我们的苗勒管退化的GRN阐明了需要确定苗勒管间充质特异性转录增强子Amhr 2。该提案使用体内转基因小鼠试验和苗勒管间充质细胞中的ATAC-seq开放染色质评估来鉴定苗勒管退化的Amhr 2转录所需的顺式元件。这些知识应该告知GRN的苗勒管回归，并可能提供新的见解人类DSD的起源。