Gene Regulatory Networks for Mullerian Duct Regression

哺乳动物，包括人类，在完全分化为雄性或雌性之前，都会发育雄性和雌性生殖道器官的祖组织。男性生殖道的祖组织被称为沃尔夫管，女性生殖道的祖组织被称为<s:1>勒氏管。Wolffian管进一步分化为输精管、附睾和精囊，而llerian管进一步分化为输卵管、子宫和上阴道。男性性别分化的一个重要步骤是腋管的退化。这种退化始于胚胎发育约12.5天（E12.5）时胎儿睾丸中抗<s:1>勒氏杆菌激素（Amh）的转录，并在E17.5时接近完成。众所周知，<s:1>勒氏管退化需要AMH从胎儿睾丸释放后与其在<s:1>勒氏管间质中的主要受体AMHR2结合。实验证明，不表达Amh或Amhr2的雄性基因敲除小鼠没有经历<s:1>勒氏管退化。因此，Amh/Amhr2对男性性别分化至关重要。没有功能性AMH或AMHR2的男性患者有子宫，这种情况被称为持续性<s:1>勒氏管综合征（PMDS），一种性别发育差异（DSD）。Amhr2表达于腋管间充质细胞、支持细胞、间质细胞和出生后颗粒细胞。Amhr2的转录调控已经在体外的支持细胞、间质细胞和颗粒细胞中进行了研究。我们描述了一个基因调控网络（GRN）为<s:1>勒氏管回归。我们的<s:1>勒氏管回归GRN已经阐明了鉴定Amhr2的<s:1>勒氏管间质特异性转录增强子的必要性。本研究采用体内转基因小鼠实验和<s:1>勒氏管间质细胞的ATAC-seq开放染色质评估来鉴定<s:1>勒氏管回归中Amhr2转录所需的顺式元件。这一知识应该为<s:1>勒氏管回归的GRN提供信息，并可能为人类dsd的起源提供新的见解。

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.