AUTHOR=Eliason Steve , Sharp Thad , Sweat Mason , Sweat Yan Y. , Amendt Brad A. 

TITLE=Ectodermal Organ Development Is Regulated by a microRNA-26b-Lef-1-Wnt Signaling Axis

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00780

DOI=10.3389/fphys.2020.00780

ISSN=1664-042X

ABSTRACT=<p>The developmental role of <italic>Lef-1</italic> in ectodermal organs has been characterized using <italic>Lef-1</italic> murine knockout models. We generated a <italic>Lef-1</italic> conditional over-expression (COEL) mouse to determine the role of <italic>Lef-1</italic> expression in epithelial structures at later stages of development after endogenous expression switches to the mesenchyme. <italic>Lef-1</italic> over expression (OE) in the oral epithelium creates a new dental epithelial stem cell niche that significantly increases incisor growth. These data indicate that <italic>Lef-1</italic> expression is switched off in the dental epithelial at early stages to maintain the stem cell niche and regulate incisor growth. Bioinformatics analyses indicated that <italic>miR-26b</italic> expression increased coinciding with decreased <italic>Lef-1</italic> expression in the dental epithelium. We generated a murine model over-expressing <italic>miR-26b</italic> that targets endogenous <italic>Lef-1</italic> expression and <italic>Lef-1</italic>-related developmental mechanisms. <italic>miR-26b</italic> OE mice have ectodermal organ defects including a lack of incisors, molars, and hair similar to the <italic>Lef-1</italic> null mice. <italic>miR-26b</italic> OE rescues the <italic>Lef-1</italic> OE phenotype demonstrating a critical genetic and developmental role for <italic>miR-26b</italic> in the temporal and spatial expression of <italic>Lef-1</italic> in epithelial tissues. <italic>Lef-1</italic> expression regulates Wnt signaling and Wnt target genes as well as cell proliferation mechanisms, while <italic>miR-26b</italic> OE reduced the levels of Wnt target gene expression. The extra stem cell compartment in the <italic>COEL</italic> mice expressed <italic>Lef-1</italic> suggesting that <italic>Lef-1</italic> is a stem cell factor, which was absent in the <italic>miR-26b OE/COEL</italic> rescue mice. This is the first demonstration of a microRNA OE mouse model that has ectodermal organ defects. These findings demonstrate that the levels of <italic>Lef-1</italic> are critical for development and establish a role for <italic>miR-26b</italic> in the regulation of ectodermal organ development through the control of <italic>Lef-1</italic> expression and an endogenous stem cell niche.</p>