Abstract
BackgroundMüllerian 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.ResultsThis 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.ConclusionsThis 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.
Highlights
Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates
Some chromosomal deletions have been associated with MRKH that include loss-of-function mutations in genes such as LIM1 (LIM Homeobox 1), WNT4 and WNT9B, all of which are critical for embryonic Müllerian duct formation [12,13,14,15,16]
Based on static comparisons (E4.5-Ant, E5.5 and E6.5 ducts vs control tissue) gene ontology and pathway analysis revealed enrichment for developmental pathways associated with cell adhesion, cell migration and proliferation, Extracellular signal-Regulated Kinases (ERK) and Winglessrelated integration site (WNT) signaling, and axonal guidance (Fig. 2a and b)
Summary
Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates. Some chromosomal deletions have been associated with MRKH that include loss-of-function mutations in genes such as LIM1 (LIM Homeobox 1), WNT4 and WNT9B, all of which are critical for embryonic Müllerian duct formation [12,13,14,15,16]. Another Müllerian-linked anomaly, Hand-Foot-Genital (HFG) is associated in some cases with HOXA13 lesions (duplications or polyalanine expansions) [17, 18]. There is a need for greater understanding of the developmental pathways leading to normal Müllerian duct formation and its disorders
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