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

Caddy, Jacinta; Wilanowski, Tomasz; Darido, Charbel; Dworkin, Sebastian; Ting, Stephen B.; Zhao, Quan; Rank, Gerhard; Auden, Alana; Srivastava, Seema; Papenfuss, Anthony T.; Murdoch, J.; Humbert, Patrick O.; Parekh, Vishwas; Boulos, Nidal; Weber, Thomas; Zuo, Jian; Cunningham, John M.; Jane, Stephen M.

doi:10.1016/j.devcel.2010.08.003

Cited by 51 publications

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“…Mammalian Grhl3 has been shown to be required for the keratinocyte wound closure in tissue culture, mainly through its activation of RhoGEF19 (8). However, in Drosophila, we found that the wound closure phenotypes between wild-type and grh IM homozygous embryos were indistinguishable (Fig.…”

Section: Discussionmentioning

confidence: 71%

“…In both Drosophila and mouse, transcription factors of the Grainy head (GRH) family have been shown to be essential for the development of epithelial barriers as well as the repair of barriers after wounding (3)(4)(5)(6)(7)(8). There is also evidence from studies in Caenorhabditis elegans, Xenopus laevis, and Danio rerio indicating that GRH proteins have an evolutionarily conserved role in the development and maintenance of epidermal barrier structure (9)(10)(11).…”

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confidence: 91%

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Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

Kim

McGinnis

2010

Proc. Natl. Acad. Sci. U.S.A.

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Grainy head (GRH) is a key transcription factor responsible for epidermal barrier formation and repair, whose function is highly conserved across diverse animal species. However, it is not known how GRH function is reactivated to repair differentiated epidermal barriers after wounding. Here, we show that GRH is directly regulated by extracellular signal-regulated kinase (ERK) phosphorylation, which is required for wound-dependent expression of GRH target genes in epidermal cells. Serine 91 is the principal residue in GRH that is phosphorylated by ERK. Although mutations of the ERK phosphorylation sites in GRH do not impair its DNA binding function, the ERK sites in GRH are required to activate Dopa decarboxylase (Ddc) and misshapen (msn) epidermal wound enhancers as well as functional regeneration of an epidermal barrier upon wounding. This result indicates that the phosphorylation sites are essential for damaged epidermal barrier repair. However, GRH with mutant ERK phosphorylation sites can still promote barrier formation during embryonic epidermal development, suggesting that ERK sites are dispensable for the GRH function in establishing epidermal barrier integrity. These results provide mechanistic insight into how tissue repair can be initiated by posttranslational modification of a key transcription factor that normally mediates the developmental generation of that tissue.embryo | Drosophila | cuticle

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Section: Discussionmentioning

confidence: 71%

mentioning

confidence: 91%

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

Kim

McGinnis

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…4 Diverse physiological processes including embryonic development, chemotaxis, immune function, inflammatory responses, and wound healing require cellular polarity and motility. [5][6][7] In response to a scratch wound, the planar cell polarity requires alignment of the Golgi apparatus within the axis of secretion. 7 The leading edge relies on this constant feeding, resulting in growth and extension at the wound margin.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] In response to a scratch wound, the planar cell polarity requires alignment of the Golgi apparatus within the axis of secretion. 7 The leading edge relies on this constant feeding, resulting in growth and extension at the wound margin. 8,9 RELEVANT BASIC SCIENCE CONTEXT Cells migrate directionally in response to a variety of signals, including gradients of chemokines, growth factors, or extracellular matrix molecules.…”

Section: Introductionmentioning

confidence: 99%

Golgi Feels Its Own Wound

Darido

Jane

2013

Advances in Wound Care

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“…Epidermal acidification, homeostatic maintenance and preservation of the stratum corneum organisation are therefore perturbed, leading to pup dehydration and death immediately following birth [42], [45]. Grhl3 is also involved in wound repair regulation through the transcription of another target genes, RhoGEF19 [46]. Loss of Grhl3 leads to downregulation of RhoGEF19 expression, resulting in the disruption of planar cell polarity as well as defects in directional cell movement to heal embryonic wounds [47].…”

Section: Grhl3 Is Expressed In the Differentiated Supra-basal Compartmentioning

confidence: 99%

Long-Lived Epidermal Cancer-Initiating Cells

Youssef

Cuddihy

Darido

2017

Preprint

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Non-melanomatous skin cancers (NMSCs), which include basal and squamous cell carcinoma (BCC and SCC respectively), represent a significant burden on the population as well as an economic load to the health care system, yet treatments of these preventable cancers remain ineffective. Although primary prevention is possible through minimising sunlight exposure, the World Health Organisation estimates that between 2 and 3 million new cases of NMSCs are diagnosed each year, accounting for 1 in 3 of all newly diagnosed cancers.Furthermore, studies have estimated there has been a 2-fold increase in the incidence of NMSCs between 1960s and 1980s. The increase in cases of NMSCs as well as the lack of effective treatments makes the need for novel therapeutic approaches all the more necessary.To rationally develop more targeted treatments for NMSCs, a better understanding of the cell of origin, in addition to the underlying pathophysiological mechanisms that govern the development of these cancers, is urgent. NMSCs are generally thought to arise from specific types of stem cells that become the source of clonal expansion of tumourigenic cells. Previous research on SCC has alluded to these stem cells being localised in the basal compartment of the skin, which ordinarily houses the progenitor cells that contribute towards wound healing and normal cell turnover of overlying epidermal skin layers. More recent research has Preprints (www.preprints.org) | NOT PEER-REVIEWED |

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

Cited by 51 publications

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Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

Phosphorylation of Grainy head by ERK is essential for wound-dependent regeneration but not for development of an epidermal barrier

Golgi Feels Its Own Wound

Long-Lived Epidermal Cancer-Initiating Cells

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