Kindt Lexy M, Coughlin Alicia R, Perosino Tianna R, Ersfeld Haley N, Hampton Marshall, Liang Jennifer O
Department of Biology, University of Minnesota Duluth, Duluth.
Integrated Biosciences Graduate Program, University of Minnesota, Duluth.
Genesis. 2018 Mar;56(3):e23096. doi: 10.1002/dvg.23096. Epub 2018 Mar 10.
Anencephaly is a fatal human neural tube defect (NTD) in which the anterior neural tube remains open. Zebrafish embryos with reduced Nodal signaling display an open anterior neural tube phenotype that is analogous to anencephaly. Previous work from our laboratory suggests that Nodal signaling acts through induction of the head mesendoderm and mesoderm. Head mesendoderm/mesoderm then, through an unknown mechanism, promotes formation of the polarized neuroepithelium that is capable of undergoing the movements required for closure. We compared the transcriptome of embryos treated with a Nodal signaling inhibitor at sphere stage, which causes NTDs, to embryos treated at 30% epiboly, which does not cause NTDs. This screen identified over 3,000 transcripts with potential roles in anterior neurulation. Expression of several genes encoding components of tight and adherens junctions was significantly reduced, supporting the model that Nodal signaling regulates formation of the neuroepithelium. mRNAs involved in Wnt, FGF, and BMP signaling were also differentially expressed, suggesting these pathways might regulate anterior neurulation. In support of this, we found that pharmacological inhibition of FGF-receptor function causes an open anterior NTD as well as loss of mesodermal derivatives. This suggests that Nodal and FGF signaling both promote anterior neurulation through induction of head mesoderm.
无脑畸形是一种致命的人类神经管缺陷（NTD），其中前神经管保持开放状态。Nodal信号传导减弱的斑马鱼胚胎表现出与无脑畸形类似的开放前神经管表型。我们实验室之前的研究表明，Nodal信号通过诱导头部中胚层和中胚层起作用。然后，头部中胚层/中胚层通过未知机制促进极化神经上皮的形成，该神经上皮能够进行闭合所需的运动。我们将在球囊期用Nodal信号抑制剂处理的胚胎（会导致NTD）的转录组与在30%外包期处理的胚胎（不会导致NTD）的转录组进行了比较。该筛选鉴定出3000多个在前神经胚形成中可能起作用的转录本。几个编码紧密连接和黏着连接成分的基因的表达显著降低，支持了Nodal信号调节神经上皮形成的模型。参与Wnt、FGF和BMP信号传导的mRNA也有差异表达，表明这些信号通路可能调节前神经胚形成。为此，我们发现药理学抑制FGF受体功能会导致开放的前NTD以及中胚层衍生物的丧失。这表明Nodal和FGF信号都通过诱导头部中胚层促进前神经胚形成。
