Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, VIC, 3800, Australia.
BMC Genomics. 2020 Oct 2;21(1):688. doi: 10.1186/s12864-020-07106-8.
Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates. Many disorders of female reproduction can be attributed to anomalies of Müllerian duct development. However, the molecular genetics of Müllerian duct formation is poorly understood and most disorders of duct development have unknown etiology. In this study, we describe for the first time the transcriptional landscape of the embryonic Müllerian duct, using the chicken embryo as a model system. RNA sequencing was conducted at 1 day intervals during duct formation to identify developmentally-regulated genes, validated by in situ hybridization.
This analysis detected hundreds of genes specifically up-regulated during duct morphogenesis. Gene ontology and pathway analysis revealed enrichment for developmental pathways associated with cell adhesion, cell migration and proliferation, ERK and WNT signaling, and, interestingly, axonal guidance. The latter included factors linked to neuronal cell migration or axonal outgrowth, such as Ephrin B2, netrin receptor, SLIT1 and class A semaphorins. A number of transcriptional modules were identified that centred around key hub genes specifying matrix-associated signaling factors; SPOCK1, HTRA3 and ADGRD1. Several novel regulators of the WNT and TFG-β signaling pathway were identified in Müllerian ducts, including APCDD1 and DKK1, BMP3 and TGFBI. A number of novel transcription factors were also identified, including OSR1, FOXE1, PRICKLE1, TSHZ3 and SMARCA2. In addition, over 100 long non-coding RNAs (lncRNAs) were expressed during duct formation.
This study provides a rich resource of new candidate genes for Müllerian duct development and its disorders. It also sheds light on the molecular pathways engaged during tubulogenesis, a fundamental process in embryonic development.
苗勒氏管是成对的胚胎管，在脊椎动物中发育为女性生殖道。许多女性生殖系统疾病可归因于苗勒氏管发育异常。然而，苗勒氏管形成的分子遗传学知之甚少，大多数导管发育障碍的病因不明。在这项研究中，我们首次描述了胚胎苗勒氏管的转录图谱，使用鸡胚作为模型系统。在导管形成过程中每隔一天进行 RNA 测序，以鉴定发育调控基因，并通过原位杂交进行验证。
这项分析检测到数百个在导管形态发生过程中特异性上调的基因。基因本体论和途径分析显示，与细胞黏附、细胞迁移和增殖、ERK 和 WNT 信号通路相关的发育途径富集，有趣的是，还有轴突导向。后者包括与神经元细胞迁移或轴突生长相关的因子，如 Ephrin B2、netrin 受体、SLIT1 和 A 类 semaphorin。确定了几个以特定基质相关信号因子的关键枢纽基因为中心的转录模块；SPOCK1、HTRA3 和 ADGRD1。在苗勒氏管中还鉴定了几个新的 WNT 和 TFG-β 信号通路调节剂，包括 APCDD1 和 DKK1、BMP3 和 TGFBI。还鉴定了几个新的转录因子，包括 OSR1、FOXE1、PRICKLE1、TSHZ3 和 SMARCA2。此外，在导管形成过程中表达了 100 多个长非编码 RNA（lncRNA）。
这项研究为苗勒氏管发育及其疾病提供了丰富的候选基因资源。它还揭示了在管状发生过程中涉及的分子途径，管状发生是胚胎发育的基本过程。
