Cultured Epidermal Melanocytes from Patients with Neurofibromatosis 1 (Recklinghausen’s Disease): a Cell Culture Model for Neurofibromatosis 1

Abstract

As derivatives of the neural crest, epidermal melanocytes belong to the cell populations which are directly affected by gene defects causing neurofibromatosis 1 (NF1): increased café-au-lait macules (CALM), shifted melanin unit, and increased melanin-macroglobules in vivo. In vitro, melanocytes from the normally pigmented skin of NF 1 patients show an increased melanin content, and an additional increase of melanin content is found in melanocytes derived from CALM of these patients. In a similar two-step manner, NF 1 melanocytes contain a higher number of large melanosome complexes and of melanosomes, and tyrosine hydroxylase activity is increased. NF 1 melanocytes incorporate higher amounts of dopa, their growth rate is lower, and most of them do not achieve a normal in vitro life span. Omission from the culture medium of the tumor promotor PMA, a strong inducer of protein kinase C (PKC), brings about a comparable increase in melanin content in all three kinds of melanocyte cultures. Under this condition NF 1 melanocytes alter their morphology faster than control melanocytes. We conclude that melanogenesis and growth in NF 1 melanocytes are effected by defective alleles of the NF 1 gene, and that differences in melanogenesis between NF 1 melanocytes and controls persist also in the absence of PMA-mediated PKC stimulation.

According to the recommandations made by the National Institues of Health (NIH), at the consensus Development Conference in July, 1987, there are seven distinct forms of neurofibromatosis (NF): NF 1-NF 7 [26]. NF 1 has also been referred to as von Recklinghausen’s neurofibromatosis, or peripheral NF. NF 1 is a heritable disorder with an autosomal dominant mode of transmission (frequency 1:4000), high penetrance, and variable expressivity. The NF 1 gene has been localized at chromosome 17q11.2 [22], and its size, structure, and expression have recently become amenable to detailed molecular analysis [4, 5, 27–30]. NF 2 (frequency 1:40000) has been (frequency 1:40000) has been called central NF, or called central NF, or bilateral acoustic NF. The gene for NF 2 is located on the long arm of chromosome 22 [24]. The other forms of NF are very rare (NF 3, a mixed form with symptoms from NF 1 and NF 2; NF 5, also called segmental neurofibromatosis).