Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

Shahbazi, Marta; Peña-Jiménez, Daniel; Antonucci, Francesca; Drosten, Matthias; Pérez-Moreno, Mirna

doi:10.1242/dev.150532

Cited by 2 publications

(3 citation statements)

References 28 publications

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“…A recent study showed that CLASP2 is intimately associated with the basal proliferative make up of keratinocytes. 39 Therefore, our in vivo study results might reflect the effects of CLASP2 on keratinocyte migration, as well as its proliferation during the wound healing process. We demonstrated that CLASP2 is an effective mediator of keratinocyte migration, which plays a very important role in the primary wound healing process and is initiated by wound contraction.…”

Section: Discussionmentioning

confidence: 94%

“…CLASP2 has been associated with migratory and microtubule stabilization in several studies involving epidermal cells, fibroblasts, and neuronal dendrites. 33,39 It is very likely that this interactive mechanism is Figure 10. Schematic diagram of possible interactions between CLASP2 related factors, such as CLIP-170, EB1, and IQGAP-1, and the AKAP220 complex.…”

Section: Discussionmentioning

confidence: 99%

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Exogenous CLASP2 protein treatment enhances wound healing in vitro and in vivo

Kim

Lee

Yoo

et al. 2019

Wound Repair Regeneration

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Proliferative and migratory abilities of fibroblasts are essential for wound healing at the skin surface. Cytoplasmic linker‐associated protein‐2 (CLASP2) was originally found to interact with cytoplasmic linker protein (CLIP)‐170. CLASP2 plays an important role in microtubule stabilization and the microtubule‐stabilizing activity of CLASP2 depends on its interactions with end binding (EB)‐1 and CLIP‐170. Although the microtubule‐stabilizing role of CLASP2 is well established, the effects of CLASP2 on the migration and proliferation of fibroblasts remain unclear in the context of wound healing. Therefore, we tested the utilization of CLASP2 as a directly applied protein drug to improve wound healing by promoting the migration of effector cells, including skin fibroblasts, to the site of repair or injury using an in vivo excisional wound mouse model and in vitro Hs27 skin fibroblast model. Epidermal growth factor, which is a recognized contributor to cell proliferation and migration, was used as positive control. In vitro and in vivo, CLASP2 treatment significantly enhanced cell migration and accelerated wound closure. Furthermore, in vivo, the CLASP2‐treated animal group displayed enhanced epidermal repair and collagen deposition. Next, we studied the mechanism of CLASP2 for wound healing. Increasing the abundance of intracellular free CLASP2 in skin fibroblasts by supplying exogenous CLASP2 seemed to stabilize microtubules through an interaction between CLASP2 and CLIP‐170, as well as EB1. Exogenous CLASP2 also showed direct binding with IQGAP1, increasing both cyclic adenosine monophosphate activity and phosphorylation of glycogen synthase kinase 3β, which in turn reinstated the binding between free CLASP2 and IQGAP1. In summary, exogenous CLASP2 increased Hs27 skin fibroblast migration by interacting with IQGAP1 and other cytoskeletal linker proteins, such as CLIP‐170 and EB1. Our results strongly suggest that CLASP2 can be developed in wound healing drugs for skin repair and/or regenerating cosmetic products.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Exogenous CLASP2 protein treatment enhances wound healing in vitro and in vivo

Kim

Lee

Yoo

et al. 2019

Wound Repair Regeneration

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“…Evidence emerges connecting DNA damage and aneuploidy with reduced self-renewal capacity and increased differentiation in flies 29 and mammals 30,31 . Recent studies in mouse skin and cultured keratinocytes associated DNA damage accumulation with keratinocyte differentiation 6,32 .…”

Section: Low Contractility Upon Par3 Loss Drives Ectopic Differentiatmentioning

confidence: 99%

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

Gomes

Letzian

Saynisch

et al. 2018

Preprint

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Epithelial homeostasis requires balanced progenitor cell proliferation and differentiation, whereas disrupting this equilibrium fosters degeneration or cancer. Here we studied how cell polarity signaling orchestrates epidermal self-renewal and differentiation. Using genetic ablation, quantitative imaging, mechanochemical reconstitution and atomic force microscopy, we find that mammalian Par3 couples genome integrity and epidermal fate through shaping keratinocyte mechanics, rather than mitotic spindle orientation. Par3 inactivation impairs actomyosin contractility and viscoelasticity, and elicits mitotic failures that trigger aneuploidy, mitosisdependent DNA damage responses, p53 stabilization and premature differentiation. Importantly, reconstituting myosin activity is sufficient to restore mitotic fidelity, genome integrity, and balanced differentiation and stratification. Collectively, this study deciphers a mechanical signaling network in which Par3 acts upstream of Rho/ROCK-mediated actomyosin contractility to promote intrinsic force generation, thereby maintaining mitotic accuracy and cellular fitness at the genomic level. Disturbing this network may compromise not only epidermal homeostasis but potentially also that of other self-renewing epithelia.

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Clasp2 ensures mitotic fidelity and prevents differentiation of epidermal keratinocytes

Cited by 2 publications

References 28 publications

Exogenous CLASP2 protein treatment enhances wound healing in vitro and in vivo

Exogenous CLASP2 protein treatment enhances wound healing in vitro and in vivo

Polarity signaling ensures epidermal homeostasis by coupling cellular mechanics and genomic integrity

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