Localization of neurofibromin to keratinocytes and melanocytes in developing rat and human skin

Pigmentation defects are common in the inherited disease type 1 neurofibromatosis (NF1), predicting a role for the NF1 gene product, neurofibromin, in the skin. We used immunohistochemistry to determine the distribution of neurofibromin in normal developing and adult rat skin, normal neonatal and adult human skin, and skin from patients affected with NF1. The distribution of NF1 mRNA in the epidermis was also analyzed by in situ hybridization. NF1 mRNA and neurofibromin are highly enriched in the keratinocytes in the stratum spinosum of the epidermis in the embryonic, but not adult, rat and in both neonatal and adult humans. Immunoelectron microscopic analysis confirmed that neurofibromin is associated with the keratinocyte plasma membrane, particularly adjacent to desmosomes. Neurofibromin is also detectable in human melanocytes. Analysis of skin from NF1 patients showed normal neurofibromin expression in nine of ten hyperpigmented cafe-au-lait macules and in adjacent unaffected skin. We conclude that 1) neurofibromin expression in the perinatal rat closely parallels expression in the human; 2) reduction in detectable neurofibromin cannot be used to distinguish NF1 and normal human skin; and 3) neurofibromin might function in keratinocytes, as well as melanocytes.