Ectodermal Organ Development Is Regulated by amicroRNA-26b-Lef-1-WntSignaling Axis
Ectodermal Organ Development Is Regulated by amicroRNA-26b-Lef-1-WntSignaling Axis
复制标题
DOI：
10.3389/fphys.2020.00780
复制
发表时间：
2020-07-14
影响因子：
4
通讯作者：
Amendt, Brad A.
中科院分区：
文献类型：
--
作者：
Eliason, Steve;Sharp, Thad;Amendt, Brad A.
Lef-1在外胚层器官中的发育作用已经用Lef-1敲除小鼠模型表征。我们培育了一只Lef-1条件性过表达（COEL）小鼠，以确定Lef-1在口腔上皮中的过表达（OE）能产生一个新的牙齿上皮干细胞小生境，显著促进切牙生长。这些数据表明，Lef-1的表达在牙齿上皮细胞的早期阶段被关闭，以维持干细胞龛和调节切牙生长。生物信息学分析表明，miR-26 b在牙上皮中的表达增加与Lef-1的表达减少相一致。我们建立了一个过表达miR-26 b的小鼠模型，该模型针对内源性Lef-1表达和Lef-1相关的发育机制。miR-26 bOE拯救了Lef-1 OE表型，证明了miR-26在上皮组织中Lef-1的时空表达中的关键遗传和发育作用。1表达调节Wnt信号转导和Wnt靶基因以及细胞增殖机制，而miR-26 bOE降低Wnt靶基因的表达水平。COEL小鼠的额外干细胞区室表达Lef-1，表明Lef-1是一种干细胞因子，而在miR-26 b OE/COEL拯救小鼠中不存在。这是第一次证明具有外胚层器官缺陷的microRNA OE小鼠模型。这些发现表明，Lef-1的水平是至关重要的发展，并建立了一个作用，通过控制Lef-1的表达和内源性干细胞生态位的外胚层器官发育的调控中的作用。
The developmental role ofLef-1in ectodermal organs has been characterized usingLef-1murine knockout models. We generated aLef-1conditional over-expression (COEL) mouse to determine the role ofLef-1expression in epithelial structures at later stages of development after endogenous expression switches to the mesenchyme.Lef-1over expression (OE) in the oral epithelium creates a new dental epithelial stem cell niche that significantly increases incisor growth. These data indicate thatLef-1expression is switched off in the dental epithelial at early stages to maintain the stem cell niche and regulate incisor growth. Bioinformatics analyses indicated thatmiR-26bexpression increased coinciding with decreasedLef-1expression in the dental epithelium. We generated a murine model over-expressingmiR-26bthat targets endogenousLef-1expression andLef-1-related developmental mechanisms.miR-26bOE mice have ectodermal organ defects including a lack of incisors, molars, and hair similar to theLef-1null mice.miR-26bOE rescues theLef-1OE phenotype demonstrating a critical genetic and developmental role formiR-26bin the temporal and spatial expression ofLef-1in epithelial tissues.Lef-1expression regulates Wnt signaling and Wnt target genes as well as cell proliferation mechanisms, whilemiR-26bOE reduced the levels of Wnt target gene expression. The extra stem cell compartment in theCOELmice expressedLef-1suggesting thatLef-1is a stem cell factor, which was absent in themiR-26b OE/COELrescue mice. This is the first demonstration of a microRNA OE mouse model that has ectodermal organ defects. These findings demonstrate that the levels ofLef-1are critical for development and establish a role formiR-26bin the regulation of ectodermal organ development through the control ofLef-1expression and an endogenous stem cell niche.