Epigenetic Regulation of Skin Development and Regeneration by Vladimir A. Botchkarev & Sarah E. Millar

Author:Vladimir A. Botchkarev & Sarah E. Millar
Language: eng
Format: epub
ISBN: 9783319167695
Publisher: Springer International Publishing

6.2 Control of Epidermal Differentiation

Skin is the largest organ of the body and protects us from toxic and arid external hazards by establishing and maintaining the epidermal permeability barrier (EPB). Proliferating cells in the epidermal basal layer undergo stepwise terminal differentiation, giving rise to a stratified epithelium. Cells in the outermost layer of the epidermis become enucleated and form the stratum corneum, whose cells are sloughed off periodically and are replenished from the proliferative basal layer [5].

Prior in vitro studies suggested that BRM and BRG1, the two ATPases of the SWI2/SNF2 family, regulate the expression of independent sets of genes [6]. However, viability of Brm-null mice indicated that these two factors are functionally redundant in vivo and that BRG1 can compensate for loss of BRM [7]. In contrast, as fibroblasts lacking Brg1 are viable but Brg1-null embryos die very early during development (during the peri-implantation stage), BRG1 might exert cell-specific functions in early development [8].

In order to elucidate the in vivo role of these factors in the later stages of development, including in skin development and maintenance of skin homeostasis, mice bearing LoxP-flanked (floxed) Brg1-alleles were established. Brg1/SNF2α was ablated in the forming epidermis using K14-Cre [9] or K14-Cre-ERT2 [10] transgenic mice that express either the bacteriophage P1 Cre-recombinase or the ligand-dependent Cre-ERT2 recombinase driven by the human K14 promoter, which is active in the surface ectoderm and the basal layer of the epidermis [11]. BRG1 is expressed in the surface ectoderm including that of the outgrowing limbs as early as embryonic day 10 (E10) of development [12]. At E18.5, BRG1 is strongly expressed in most, if not all, basal cells, as well as in about 70% of the spinous and 30% of the granular cells of the developing epidermis. Using constitutively active Cre recombinase, Brg1 was efficiently ablated in epidermal keratinocytes and in the ectodermal layer of the limbs before E12 [12, 13]. Ablation of Brg1 in the surface ectoderm induced severe hindlimb defects due to lack of maintenance of the apical ectodermal ridge (AER). The absence of forelimb defects in constitutive Cre mutants most likely reflects the earlier development of the forelimb, which occurs before efficient expression of the Cre recombinase [14], rather than differential participation of BRG1 in fore- and hindlimb development. Hindlimb defects can be avoided by inducing Brg1 ablation in postnatal skin. Indra and co-workers demonstrated that BRG1 is dispensable for formation of embryonic epidermis, but is essential for establishment of the epidermal permeability barrier (EPB). Interestingly, temporal ablation of Brg1 in the epidermis of mice lacking BRM showed that the BRM/BRG1 ATP-dependent chromatin remodeling complex is not required for epidermal proliferation and “early” differentiation, and revealed partial redundancy between BRM and BRG1 in regulating “late” terminal differentiation of the epidermal keratinocytes E12 [13].

Taken together, these results suggested that BRG1 selectively controls the expression of genes involved in the epithelial mesenchymal interactions required for limb patterning [15] and in terminal differentiation of keratinocytes during development. Similar to the situation in undifferentiated F9 embryonal carcinoma cells

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