Dual role of laminin‑511 in regulating melanocyte migration and differentiation.

Laminins are the major basement membrane (BM) components and are heterotrimers composed of an α, a β and a γ chain. In skin, laminins are present in basement membranes surrounding vascular structures, nerves, adipose tissue and in the specialized junctional BM between the epidermis and dermis. The main laminin isoforms in the dermo-epidermal BM are laminin‑332, laminin‑511 and laminin‑211, the latter being restricted to hair follicles (HFs). The laminin γ1 chain is the most abundant γ chain; its global ablation in mice leads to early embryonic lethality at E5.5. To elucidate the cellular function of the γ1 chain in skin, we generated mice with keratinocyte-specific deletion of this chain (Lamc1^EKO) by using the keratin (K)14-Cre/loxP system. These mice showed delayed coat pigmentation despite normal melanocyte counts in the skin. However, levels of differentiation-specific melanocyte enzymes TRP‑1, TRP‑2 and tyrosinase were reduced in Lamc1^EKO mice, and melanocytes failed to migrate to their differentiation niche in HFs and accumulated in the IFE. These results suggested that the pigmentation defect results from impaired melanocyte migration. The impaired migratory capacity of melanocytes is due to the altered composition of laminins in the BM of Lamc1^EKO mice: Loss of keratinocyte-derived pro-migratory laminin‑511 is not compensated by ectopically deposited fibroblast-derived laminin‑211. Furthermore, contact of melanocytes with recombinant laminin‑511, but not with laminin‑211, induces the expression of the chemokine receptor CXCR4 on melanocytes, needed for SDF‑1 (stromal cell‑derived factor‑1)-mediated migration into HFs. We here demonstrate that laminin‑511 controls the differentiation of melanocytes by regulating their migration from the epidermis into HFs and by activating CXCR4 expression on melanocytes required for their recruitment into HFs in an SDF‑1-dependent manner.

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