Deficiency in the LIM-only protein Fhl2 impairs skin wound healing.
After skin wounding, the repair process is initiated by the release of growth factors, cytokines, and bioactive lipids from injured vessels and coagulated platelets. These signal molecules induce synthesis and deposition of a provisional extracellular matrix, as well as fibroblast invasion into and contraction of the wounded area. We previously showed that sphingosine-1-phosphate (S1P) triggers a signal transduction cascade mediating nuclear translocation of the LIM-only protein Fhl2 in response to activation of the RhoA GTPase (Muller, J.M., U. Isele, E. Metzger, A. Rempel, M. Moser, A. Pscherer, T. Breyer, C. Holubarsch, R. Buettner, and R. Schule. 2000. EMBO J. 19:359-369; Muller, J.M., E. Metzger, H. Greschik, A.K. Bosserhoff, L. Mercep, R. Buettner, and R. Schule. 2002. EMBO J. 21:736-748.). We demonstrate impaired cutaneous wound healing in Fhl2-deficient mice rescued by transgenic expression of Fhl2. Furthermore, collagen contraction and cell migration are severely impaired in Fhl2-deficient cells. Consequently, we show that the expression of alpha-smooth muscle actin, which is regulated by Fhl2, is reduced and delayed in wounds of Fhl2-deficient mice and that the expression of p130Cas, which is essential for cell migration, is reduced in Fhl2-deficient cells. In summary, our data demonstrate a function of Fhl2 as a lipid-triggered signaling molecule in mesenchymal cells regulating their migration and contraction during cutaneous wound healing.
Wixler
Viktor
V
Institute of Molecular Virology, Münster University Hospital Medical School, D-48149 Münster, Germany.
Hirner
Stephanie
S
Müller
Judith M
JM
Gullotti
Lucia
L
Will
Carola
C
Kirfel
Jutta
J
Günther
Thomas
T
Schneider
Holm
H
Bosserhoff
Anja
A
Schorle
Hubert
H
Park
Jung
J
Schüle
Roland
R
Buettner
Reinhard
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D003094:Collagen / Q000378:metabolism; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060850:LIM-Homeodomain Proteins; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D012879:Skin Physiological Phenomena; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D000199:Actins; D050719:Crk-Associated Substrate Protein; C491382:Fhl2 protein, mouse; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D014157:Transcription Factors; D003094:Collagen