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Type 1 neurofibromatosis syndrome (NF1) has been linked with mutations of the NF1 gene which encodes tumor suppressor neurofibromin, a regulator of Ras-MAPK signaling. In human epidermis, keratinocytes express NF1 tumor suppressor and it may have a distinctive function in these cells during wound healing, such as regulating Ras activity. NF1 expression was first studied during the epidermal wound healing using suction blister method. NF1 gene expression increased both in hypertrophic and migrating zones of the healing epidermis, and also in dermal fibroblasts underneath the injury. This prompted us to study epidermal wound healing in NF1 patients. Wound healing efficiency was evaluated 4 days after blister induction by clinical, physiological and histological methods. Epidermal wound healing was equally effective in NF1 patients and healthy controls. In addition, dermal wound healing appears to function normally in NF1 patients based on retrospective and follow-up study of biopsy scars. Furthermore, the healing wounds were analyzed immunohistochemically for cell proliferation rate and Ras-MAPK activity. Neither epidermal keratinocytes nor dermal fibroblasts showed difference in the cell proliferation rate or Ras-MAPK activity between NF1 patients and controls. Interestingly, NF1 patients displayed increased cell proliferation rate and Ras-MAPK activity in periarteriolar tissue underneath the wound. The results of the study suggest that epidermal wound healing is not markedly altered in NF1 patients. Furthermore, NF1 protein seems not to have an important function as a Ras-MAPK regulator in epidermal keratinocytes or dermal fibroblasts but instead appears to be regulator of Ras-MAPK signaling in vascular tissues.

Background: Neurofibromatosis type 1 (NF1) protein (neurofibromin) accelerates the inactivation of Ras-GTP in various cell types. Somatic mutations of the NF1 gene may lead to malignant transformation and uncontrolled proliferation. We have previously shown that NF1 protein expression is downregulated in psoriasis in vivo., Objectives: To study the functional expression and distribution of NF1 mRNA and protein in vivo and in psoriatic and normal keratinocyte cultures., Methods: Immunohistochemistry and in situ hybridization were used to study NF1 gene and protein expression in psoriasis in vivo. Furthermore, Northern and in situ hybridizations, immunoblot and localization analyses were utilized to study NF1 mRNA and protein in vitro in keratinocyte cultures., Results: NF1 tumour suppressor gene expression was reduced in lesional psoriatic skin compared with perilesional and normal skin in vivo. The in vitro results showed that the levels of NF1 mRNA and protein were reduced in cultured psoriatic keratinocytes during cellular differentiation even after multiple passaging of the cells. Moreover, cultured nonlesional psoriatic keratinocytes were almost equally defective as lesional cells with respect to NF1 expression., Conclusions: Our findings demonstrate that psoriatic keratinocytes maintain an altered phenotype and gene expression profile even when isolated from interaction with lymphocytes and fibroblasts, which are known to increase proliferation of keratinocytes. As NF1 protein is regarded as a Ras proto-oncogene regulator, the aberrant expression and distribution of NF1 protein and mRNA found in the present study may be causative to the previously described increased activation of Ras in psoriatic lesions, and relate to altered cellular behaviour.

Mutations of the NF1 tumor suppressor gene cause type 1 neurofibromatosis, characterized by multiple tumors of the peripheral nerves, as well as other tumor types. The NF1 protein, neurofibromin, is intricately linked to the cell growth regulatory signalling pathways, e.g. by possessing RAS-GTPase activity. The regulation and role of neurofibromin are not known in normal human development. We addressed this issue by studying the regulation of neurofibromin in normal human peripheral nerves, from early fetal development to adulthood. The barely detectable neurofibromin immunosignal in peripheral nerves during the first trimester of gestation contrasted dramatically to its increase in Schwann cells, perineurial cells, and axons during the second and third trimesters. Interestingly, the type I and II isoforms of neurofibromin, differing in their RAS oncoprotein inactivation capacity, displayed clearly different expression profiles throughout these periods. This suggests distinct cellular functions for these neurofibromin isoforms. The results also revealed distinct species-specific differences in neurofibromin expression, potentially bearing relevance to the lack of human neurofibromatosis-like disorders in other species.