Hmga2-dependent cAMP signaling drives UVB-induced melanocyte stem cell activation

Ultraviolet-B irradiation (UVB) induces an epidermal damage response including keratinocyte hyperplasia, immune cell infiltration, and the recruitment of follicular melanocyte stem cells to the interfollicular epidermis. Here, we establish the oncofetal chromatin remodeling factor High mobility group AT-hook 2 (Hmga2) as a regulator of these phenotypes through a cyclic-AMP (cAMP) driven process. In this study, we identify somatic tissue expression of Hmga2 in the basal layer of hyperplastic UVB-exposed keratinocytes. Loss of Hmga2 results in the near absence of epidermal hyperplasia, cutaneous neutrophil infiltration, and melanocyte stem cell migration to the interfollicular epidermis. RNAseq of UVB-exposed keratinocytes from wild-type and Hmga2 loss-of-function models reveals increased expression of Adenosine A1 receptor (Adora1), a negative regulator of cAMP. Administration of the cAMP pathway activator forskolin to Hmga2-/- animals is sufficient to rescue McSC migration, thus highlighting the Hmga2-cAMP axis as a regulator in the cutaneous UVB response.