Global Deletion of Ankrd1 Results in a Wound-Healing Phenotype Associated with Dermal Fibroblast Dysfunction

Abstract

The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These in vitro data were consistent with in vivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both in vitro and in vivo.

Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential

“…Indeed, ANKRD1 is strongly elevated after wounding which suggests its role in the healing process [ 37 ]. Furthermore, it was recently shown that wound closure was significantly delayed in Ankrd1 knockout mice [ 38 ], lending further support to the role of ANKRD1 in tissue repair.…”

“…Early work indicated the role of ANKRD1 in non-cardiac fibrotic responses where ANKRD1 transcripts and proteins are highly induced after dermal wounding in mice and its over-expression enhanced the healing process [ 37 ]. Moreover, Ankrd1 -knockout mice have been shown to be viable but display impaired wound healing that is characterized by dermal fibroblast dysfunction [ 38 ]. There is evidence that nuclear ANKRD1, in concert with nucleolin, functions in the wound repair process and modulates ECM remodeling via transcriptional regulation of matrix metalloproteinases gene expression [ 28 ].…”

Anti-Aging Effects of Leontopodium alpinum (Edelweiss) Callus Culture Extract through Transcriptome Profiling

“…ID3 acts as a transcriptional regulator inhibiting stem cell differentiation and promoting cell cycle progression [47]. In addition, a recent study showed that the loss of ANKRD1 function in mice resulted in delayed wound healing, suggesting its role in wounding and tissue injury [49]. Furthermore, Rho-related BTB domain-containing 3 (RHOBTB3) functions to promote the proteasomal degradation of hypoxia-inducible factors (HIFs), which are the main regulators of adaptive responses to low oxygen [50].…”

Comparative Transcriptomics Identifies Novel Genes and Pathways Involved in Post-Traumatic Osteoarthritis Development and Progression

“…Ankrd1 , a transcriptional repressor of MMP13 [ 28 ], was highly upregulated in MRL/MpJ at 1-day post-injury, whereas only moderately changed in C57BL/6J and STR/ort ( Figure 4 B). Global deletion of Ankrd1 resulted in delayed excisional wound closure [ 29 ]. Deletion of Ankrd1 also resulted in moderate downregulation of Mmp2 and Mmp14 [ 28 ].…”