Merkel nerve endings are mechanoreceptors in the mammalian skin. They consist of large, pale cells with lobulated nuclei forming synapse-like contacts with enlarged terminal endings of myelinated nerve fibers. They were first described by F.S. Merkel in 1875. They are found in the skin and in those parts of the mucosa derived from the ectoderm. In mammals (apart from man), the largest accumulation of Merkel nerve endings is found in whiskers. In all vertebrates, Merkel nerve endings are located in the basal layer of the epidermis, apart from birds, where they are located in the dermis. Cytoskeletal filaments consisting of cytokeratins and osmiophilic granules containing a variety of neuropeptides are found in Merkel cells. In anseriform birds, groups of cells resembling Merkel cells, with discoid nerve terminals between cells, form Grandry corpuscles. There has been controversy over the origin of Merkel cells. Results from chick/quail chimeras show that, in birds, Merkel cells are a subpopulation of cells derived from the neural crest, which thus excludes their development from the epidermis. Most recently, also in mammals, conclusive evidence for a neural crest origin of Merkel cells has been obtained. Merkel cells and nerve terminals form mechanoreceptors. Calcium ions enter Merkel cells in response to mechanical stimuli, a process which triggers the release of calcium from intracellular stores resulting in exocytosis of neurotransmitter or neuromodulator. Recent results suggest that there may be glutamatergic transmission between Merkel cell and nerve terminal, which appears to be essential for the characteristic slowly adapting response of these receptors during maintained mechanical stimuli. Thus, we are convinced that Merkel cells with associated nerve terminals function as mechanoreceptor cells. Cells in the skin with a similar appearance as Merkel cells, but without contact to nerve terminals, are probably part of a diffuse neuroendocrine system and do not function as mechanoreceptors. Probably these cells, rather than those acting as mechanoreceptors, are the origin of a highly malignant skin cancer called Merkel cell carcinoma. Anat Rec Part A 271A: 225-239, 2003.

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Homozygosity for the Splotch mutation causes neural tube and neural crest defects in mice. It has been demonstrated that Splotch mutant mice carry mutations in the homeodomain of the Pax-3 gene. Pax-3 is expressed in the neural tube, some neural crest derivatives, the mesenchyme of the limb bud and the somites. We have examined the development of the somite-derived skeletal muscles in homozygotes carrying the Splotch (Sp1H) mutation. Our results suggest that the Splotch mutation affects the development of skeletal muscles in a region-specific way: 1. The expression of the CMZ transgene in homozygotes reveals a disorganisation of the dermomyotome in whole stained embryos. 2. The axial musculature is reduced in size along a rostro-caudal gradient. 3. The muscle anlagen in the limbs develop much more slowly. Muscles of the head and the ventral body wall are normally developed in the mutant on day 13.5 of gestation. Recently, it has been shown that the myogenic precursors of the limbs are derived from the lateral half of the somite. The specific disturbance of muscle development in the limbs of Splotch mutants thus suggests a role for Pax-3 in the organisation of the somite, the production of trophic factors in the limb mesenchyme or an alteration of myogenic and mesenchymal cells.

Here, we provide evidence for the neural crest origin of mammalian Merkel cells. Together with nerve terminals, Merkel cells form slowly adapting cutaneous mechanoreceptors that transduce steady indentation in hairy and glabrous skin. We have determined the ontogenetic origin of Merkel cells in Wnt1-cre/R26R compound transgenic mice, in which neural crest cells are marked indelibly. Merkel cells in whiskers and interfollicular locations express the transgene, beta-galactosidase, identifying them as neural crest descendants. We thus conclude that murine Merkel cells originate from the neural crest.

Nude mice have a mutation in the transcription factor Foxn1(nu), resulting in downregulation of hair keratins. Although hair follicles develop normally, the hair fibers become structurally weak, curl, and break off at the surface. Nails in nude mice are deformed, based on alterations of the onychocyte differentiation process. Elemental microanalysis of the nail plate reveals marked decreases in sulfur concentrations in the nude mouse nail plates. Immunohistochemistry shows a lack of keratin 1 expression in terminally differentiating keratinocytes of the nail matrix. Instead, the typical differentiation process of the matrix is altered toward an epidermis-like differentiation pattern, comprising the production of filaggrin-containing keratohyalin granules in cells resembling those of the stratum granulosum, which are never observed in normally haired mice. The nail plate has diffuse basophilic stippling. It is thinner than normal, weak, and in most Foxn1(nu)/Foxn1(nu) mice breaks where it separates from the hyponychium. These studies indicate that the Foxn1(nu) mutated gene has effects beyond downregulating keratin expression, including changes in filaggrin expression, and is critical for normal onycholemmal differentiation. The nails of nude mice provide new insights into the molecular controls of onychocyte differentiation, and they offer a useful model to investigate the pathogenesis of nail hypergranulosis, a common feature in human nail diseases.