Thyroid hormones (THs) are key regulators of development, tissue differentiation and maintenance of metabolic balance in virtually every cell of the body. Accordingly, severe alteration of TH action during fetal life leads to permanent deficits in humans. The skin is among the few adult tissues expressing the oncofetal protein type 3 deiodinase (D3), the TH inactivating enzyme. Here, we demonstrate that D3 is dynamically regulated during epidermal ontogenesis. To investigate the function of D3 in a post-developmental context, we used a mouse model of conditional epidermal-specific D3 depletion. Loss of D3 resulted in tissue hypoplasia and enhanced epidermal differentiation in a cell-autonomous manner. Accordingly, wound healing repair and hair follicle cycle were altered in the D3-depleted epidermis. Furthermore, in vitro ablation of D3 in primary culture of keratinocytes indicated that various markers of stratified epithelial layers were up-regulated, thereby confirming the pro-differentiative action of D3 depletion and the consequent increased intracellular T3 levels. Notably, loss of D3 reduced the clearance of systemic TH in vivo, thereby demonstrating the critical requirement for epidermal D3 in the maintenance of TH homeostasis. In conclusion, our results show that the D3 enzyme is a key TH-signaling component in the skin thereby providing a striking example of a physiological context for deiodinase-mediated TH metabolism, as well as a rationale for therapeutic manipulation of deiodinases in patho-physiological contexts.

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