TY - JOUR

T1 - Necl2 regulates epidermal adhesion and wound repair

AU - Giangreco, Adam

AU - Jensen, Kim B

AU - Takai, Yoshimi

AU - Miyoshi, Jun

AU - Watt, Fiona M

PY - 2009/10

Y1 - 2009/10

N2 - Differential expression of cell adhesion molecules regulates stem cell location, self-renewal and lineage selection under steady state conditions and during tissue repair. We show that the intercellular adhesion protein nectin-like molecule 2 (Necl2) is highly expressed in bulge stem cells of adult human and mouse hair follicles. Overexpression of Necl2 in cultured human keratinocytes led to upregulation of calcium/calmodulin-associated Ser/Thr kinase (CASK), increased calcium-independent intercellular adhesion, and inhibition of cell motility and in vitro wound healing. Although the rate of cell proliferation was reduced, terminal differentiation was unaffected. To assess the role of Necl2 in vivo, we examined the epidermis of Necl2-null mice and developed transgenic mice that expressed Necl2 in the basal layer of murine epidermis. Necl2 overexpression led to a reduction in S-phase cells and an increase in quiescent cells retaining DNA label in the bulge. Although epidermal homeostasis appeared normal in both transgenic and knockout mice, wound healing was markedly delayed. Necl2 overexpression resulted in reduced proliferation and increased levels of CASK and E-cadherin at the leading edge of healing wounds, consistent with its effects in culture. Our results demonstrate that Necl2 is involved in regulating epidermal stem cell quiescence and location.

AB - Differential expression of cell adhesion molecules regulates stem cell location, self-renewal and lineage selection under steady state conditions and during tissue repair. We show that the intercellular adhesion protein nectin-like molecule 2 (Necl2) is highly expressed in bulge stem cells of adult human and mouse hair follicles. Overexpression of Necl2 in cultured human keratinocytes led to upregulation of calcium/calmodulin-associated Ser/Thr kinase (CASK), increased calcium-independent intercellular adhesion, and inhibition of cell motility and in vitro wound healing. Although the rate of cell proliferation was reduced, terminal differentiation was unaffected. To assess the role of Necl2 in vivo, we examined the epidermis of Necl2-null mice and developed transgenic mice that expressed Necl2 in the basal layer of murine epidermis. Necl2 overexpression led to a reduction in S-phase cells and an increase in quiescent cells retaining DNA label in the bulge. Although epidermal homeostasis appeared normal in both transgenic and knockout mice, wound healing was markedly delayed. Necl2 overexpression resulted in reduced proliferation and increased levels of CASK and E-cadherin at the leading edge of healing wounds, consistent with its effects in culture. Our results demonstrate that Necl2 is involved in regulating epidermal stem cell quiescence and location.

KW - Animals

KW - Cell Adhesion

KW - Cell Adhesion Molecules

KW - Cell Differentiation

KW - Cell Proliferation

KW - Cells, Cultured

KW - Epidermis

KW - Homeostasis

KW - Humans

KW - Immunoglobulins

KW - Keratinocytes

KW - Membrane Proteins

KW - Mice

KW - Mice, Knockout

KW - Stem Cells

KW - Tumor Suppressor Proteins

KW - Up-Regulation

KW - Wound Healing

U2 - 10.1242/dev.038232

DO - 10.1242/dev.038232

M3 - Journal article

C2 - 19783739

VL - 136

SP - 3505

EP - 3514

JO - Development

JF - Development

SN - 0950-1991

IS - 20

ER -