Epidermal Wound Repair Is Regulated by the Planar Cell Polarity Signaling Pathway

Abstract

SUMMARY The mammalian PCP pathway regulates diverse developmental processes requiring coordinated cellular movement, including neural tube closure and cochlear stereociliary orientation. Here, we show that epidermal wound repair is regulated by PCP signaling. Mice carrying mutant alleles of PCP genes Vangl2, Celsr1, PTK7, and Scrb1, and the transcription factor Grhl3, interact genetically, exhibiting failed wound healing, neural tube defects and disordered cochlear polarity. Using phylogenetic analysis, ChIP, and gene expression in Grhl3−/− mice, we identified RhoGEF19, a homologue of a RhoA activator involved in PCP signaling in Xenopus, as a direct target of GRHL3. Knockdown of Grhl3 or RhoGEF19 in keratinocytes induced defects in actin polymerisation, cellular polarity and wound healing, and re-expression of RhoGEF19 rescued these defects in Grhl3-kd cells. These results define a role for Grhl3 in PCP signaling, and broadly implicate this pathway in epidermal repair.

The Scribble–Dlg–Lgl Module in Cell Polarity Regulation

“…In addition, Scribble interacts both physically and genetically with the core PCP protein Vangl2 during neural tube closure and in the development of branched structures such as the lung (Yates et al 2013;Montcouquiol et al 2003). As observed with other PCP genes such as Vangl2, Scribble can also regulate wound healing in mammals (Caddy et al 2010). The PCP role for the Scribble module appears highly conserved across species.…”

Learning from regeneration research organisms: The circuitous road to scar free wound healing

“…A benefit to using Xenopus as a model is that they are able to regenerate skin appendages, such as exocrine glands. Additionally, Xenopus have a multi-layered epidermis, similar to that of mammals (Bertolotti et al, 2013; Caddy et al, 2010; Franchini and Bertolotti, 2014; Franchini et al, 2016; Otsuka-Yamaguchi et al, 2017; Yoshii et al, 2005). Just like frogs, urodele amphibians, such as newts and axolotls, also have the ability to regenerate skin appendages scar-free (Fig.…”

Palatogenesis and cutaneous repair: A two‐headed coin

“…Like Irf6 , the Grhl3 gene is also required for proper migration of keratinocytes. However, compared to Irf6 , the absence of Grhl3 led to decreased level of active RhoA and absence of actin stress fibers (Caddy et al, 2010). In fact, RhoGEF19 , an activator of RhoA, was identified as the direct target of Grhl3 .…”