RESUMO
Laminins are the major basement membrane (BM) components and are heterotrimers composed of an α, a ß 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 laminin332, laminin511 and laminin211, 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 (Lamc1EKO) 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 TRP1, TRP2 and tyrosinase were reduced in Lamc1EKO 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 Lamc1EKO mice: Loss of keratinocyte-derived pro-migratory laminin511 is not compensated by ectopically deposited fibroblast-derived laminin211. Furthermore, contact of melanocytes with recombinant laminin511, but not with laminin211, induces the expression of the chemokine receptor CXCR4 on melanocytes, needed for SDF1 (stromal cellderived factor1)-mediated migration into HFs. We here demonstrate that laminin511 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 SDF1-dependent manner.
Assuntos
Quimiocina CXCL12/metabolismo , Laminina/genética , Laminina/metabolismo , Melanócitos/citologia , Receptores CXCR4/metabolismo , Animais , Adesão Celular , Diferenciação Celular , Movimento Celular , Técnicas de Inativação de Genes , Oxirredutases Intramoleculares/metabolismo , Queratinócitos/metabolismo , Melanócitos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Monofenol Mono-Oxigenase/metabolismo , Oxirredutases/metabolismo , Pigmentação da PeleRESUMO
Nidogen 1 and 2 are ubiquitous basement membrane (BM) components. They show a divergent expression pattern in certain adult tissues with a prominent localization of nidogen 2 in blood vessel BMs. Deletion of either nidogen 1 or 2 in mice had no effect on BM formation, suggesting complementary functions. However, studies in these mice revealed isoform-specific functions with nidogen 1-deficient mice showing neurological abnormalities and wound-healing defects not seen in the absence of nidogen 2. To investigate this further nidogen 1- or 2-deficient mice were intravenously injected with B16 murine melanoma cells, and lung metastasis was analyzed. The authors could show that loss of nidogen 2, but not of nidogen 1, significantly promotes lung metastasis of melanoma cells. Histological and ultrastructural analysis of nidogen 1- and 2-deficient lungs did not reveal differences in morphology and ultrastructure of BMs, including vessel BMs. Furthermore, deposition and distribution of the major BM components were indistinguishable between the two mouse strains. Taken together, these results suggest that absence of nidogen 2 might result in subtle changes of endothelial BMs in the lung, which would allow faster passage of tumor cells through these BMs, leading to a higher metastasis rate and more larger tumors.