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PubMed2025

Temporal gating of nuclear import: How Merkel cell polyomavirus exploits the cell cycle for nuclear entry.

Merkel cell polyomavirus (MCPyV) is a small, DNA tumor virus that is causally linked to an aggressive form of human skin cancer called Merkel cell carcinoma. MCPyV is the only polyomavirus definitively shown to cause cancer in humans, yet little is known about how it establishes infection in target cells. In this study, we report an unconventional mechanism by which MCPyV enters the host cell nucleus, where viral genome replication occurs. We demonstrate that, unlike other known polyomaviruses, MCPyV does not require the nuclear pore complex during entry. Instead, it takes advantage of cell cycle-dependent nuclear envelope breakdown to deliver its genetic material into the nucleus. We further show that the VP1 major capsid protein is sufficient to facilitate this process. Overall, our findings reveal a novel mechanism of polyomavirus nuclear entry and provide insight into the diverse mechanisms that these viruses use to cause infection.

Merkel cell polyomavirus↗

PubMed2005

Immunohistochemical reactions of receptors to met-enkephalin, VIP, substance P, and CGRP located on Merkel cells in the rat sinus hair follicle.

The role of Merkel cells in type I cutaneous mechanoreceptors remains enigmatic though mechanical transduction or neuromodulation function has been proposed. It has been shown that mammalian Merkel cells express immunohistochemical reactions of met-enkephalin, VIP, substance P, and CGRP, though the reactivity differs between species. If any one of these peptides acts as a transmitter or modulator for Merkel nerve terminals, these structures must have a specific receptor for the substance. We therefore studied the immunohistochemical localization of the above-mentioned neuropeptides and their receptors in Merkel cell-nerve endings in rat whisker pads. Specimens were doubly stained with polyclonal antibodies to neuropeptides and their receptors combined with a monoclonal antibody to cytokeratin 20, which was used for the labeling of Merkel cells. Merkel cells in the rat sinus hair follicles showed positive immunoreactions for all peptides studied, whereas the immunoreactions of receptors to these peptides were localized on Merkel cell membranes but not on the axon terminals. These results suggest that neuropeptides released from Merkel cells act on Merkel cells themselves by an autocrine mechanism.

Animals↗

PubMed2000

Postnatal differentiation of Merkel cells in the rat palatine mucosa, with special reference to the timing of peripheral nerve development and the potency of cell mitosis.

The origin and mechanism of the differentiation and proliferation of Merkel cells are enigmatic. A preliminary study in our laboratory showed that Merkel cells in the rat palatine mucosa emerge after birth. This is in contrast to the case of similar cells in the skin that differentiate during the embryonic period prior to the establishment of peripheral nerve innervation. We studied immunohistochemically the developmental timings of Merkel cells and peripheral nerves in the rat palatine mucosa using antibodies to cytokeratins 18 and 20, PGP 9.5, and CGRP using developing palates of prenatal and postnatal rats. We also studied the potency of mitosis in Merkel cells by immunohistochemistry using antibodies for a cell proliferation marker Ki67 and cyclin D-kinase inhibitors p16, p21 and p27. It was shown that Merkel cells in the rat palatine mucosa differentiate postnatally, after the development of peripheral nerve fiber terminals was almost established. The emergence and increase in number of Merkel cells progressed in an anterior-to-posterior wave. Newly appearing Merkel cells were usually negative for anti-cytokeratin 20 antibody but gained affinity for the antibody with progress of maturation. All Merkel cells in the palatine mucosa were negative for anti-Ki67 antibody but positive for anti-p27 antibody. These results indicate that Merkel cells in the rat palatine mucosa are not responsible for the development of peripheral nerve fiber terminals and that these cells differentiate in situ from intraepithelial stem cells.

Animals↗

PubMed1987

Identification of Merkel cells in oral epithelium using antikeratin and antineuroendocrine monoclonal antibodies.

Merkel cells are a rare cell type located at or near the basal lamina of oral epithelia and epidermis. They are associated with nerves, and may function as touch receptors. Merkel cells are difficult to identify by routine light microscopy, but have been identified by electron microscopy and specific antibodies. We demonstrate here that Merkel cells can be identified by immunohistochemistry, using a monoclonal antibody (LK2H11, Lloyd and Wilson, 1983) to neuroendocrine granules, and a monoclonal antibody (35 beta H11, Gown and Vogel, 1982) to a 54-kD keratin generally located in simple epithelia but not in stratified epithelia. Human oral tissue was fixed in Carnoy's fixative, and adjacent serial sections were stained with the two antibodies. Individual positively-stained cells were generally located at the bases of rete ridges. Cells in the same position in adjacent sections stained with both antibodies. Essentially all cells (94%) staining for neuroendocrine granules also gave a positive reaction for the 54-kD keratin, evidence that a single Merkel cell contains neuroendocrine granules and the 54-kD keratin. Staining of epithelial sheets of human oral tissues revealed a linear distribution of Merkel cells along the bases of rete ridges. We concluded that antibodies to simple epithelial keratins and neuroendocrine granules may be excellent immunohistochemical markers for Merkel cells, thus facilitating future studies to examine changes in Merkel cells and their distribution in pathologic conditions. The observation that Merkel cells can be stained with an antikeratin antibody strongly supports the epithelial origin of these cells.

Antibodies, Monoclonal↗

PubMed2003

Normal human Merkel cells are present in epidermal cell populations isolated and cultured from glabrous and hairy skin sites.

The Merkel cell is a highly specialized cell that primarily acts as a slowly adapting mechanoreceptor. Merkel cells are scarce in normal skin but can be identified by the expression of distinct keratin filaments. Merkel cells constitute a very unique population and many questions still remain as to their origin, number, proliferative capacity, and functions in cutaneous biology. The dissociation of epidermal cells from skin is a widely used technique to extract and culture keratinocytes. We took advantage of a two-step extraction method to quantify keratin-20-expressing Merkel cells among total cutaneous cells obtained from either hairy or glabrous skin biopsies. Flow cytometry analysis revealed that keratin-20-labeled Merkel cells represent between 3.6% and 5.7% of freshly dissociated basal epidermal cells. No significant differences were seen between samples derived from glabrous palmar and hairy anatomic sites, from children and adult, respectively. We also report on the presence of Merkel cells in primary and first subcultures of epidermal cells indicating their capacity to remain viable after extraction from skin of various anatomic sites. To our knowledge, this is the first demonstration of nontumorigenic human Merkel cells in culture in vitro. The persistence of a small number of Merkel cells in culture suggests that, with the development of appropriate culture conditions, these cells could be amplified and further studied to unravel long-standing questions relative to their paracrine function or epithelial origin.

Adult↗

PubMed2003

[Neuroendocrine tumors of visual system--Merkel cell carcinoma].

PURPOSE: To describe cases of Merkel cell carcinoma. Belonging to the APUD-system tumors, the highly malignant Merkel cell carcinoma affects in 10% the ocular adnexes, 50-60% of the patients develop a metastasis to the lymph nodes, and the five year survival rate is only 38%. 30% of the tumors recur after one year. MATERIAL AND METHODS: In the last eight years the Merkel cell carcinoma was diagnosed in four patients and was treated by wide resection, radiotherapy and cytostatic drugs. Histological and immunohistological examination was performed. RESULTS: In three cases the carcinoma was diagnosed in the upper lid and in one case in the eyebrow. Two patients could not be cured. Characteristic is clinical uniform appearance of the tumor as painless, reddish nodule with smooth surface, telangiectatic blood vessels, fast growing and fast leading to metastasis. Furthermore, the histological characteristics of the tumor were found as well as NSE, S100 proteins and neuroendocrine granula, which allow to classify to the APUD--system and to distinguish from the more benign tumors. CONCLUSIONS: As neuroendocrine tumor the Merkel cell carcinoma represents a high malignant tumor in ophthalmology. The certain diagnosis is only made by histological and immunohistological examination. A full-thickness resection followed by radiation, should be performed as soon as possible.

Aged↗

PubMed2005

Apoptosis of Merkel cells in neurotrophin-3 null mice.

Postnatal mice lacking neurotrophin-3 (NT3) are deficient in Merkel cells of touch domes and whisker follicles. We examined the mechanism of Merkel cell loss by immunocytochemistry and electron microscopy. Merkel cell of whisker follicles of NT3 null newborns exhibited decreased immunoreactivity for cytokeratin 8 and contained apoptotic bodies that were positive for cleaved caspase-3, a marker of active apoptosis. By electron microscopy, the Merkel cells displayed aggregation of chromatin along the nuclear membrane, with the marginated chromatin forming caps at the periphery of the nucleus. Ribosomes aggregated in the cytoplasm, while dense core granules characteristic of Merkel cells were still discernible. Finally, the Merkel cells and their nuclei fragmented into apoptotic bodies. None of the apoptotic Merkel cells were contacted by nerve fibers, and their desmosomal contacts with surrounding keratinocytes disappeared. After postnatal day 6 apoptotic Merkel cells were no longer observed, and the number of surviving Merkel cells was severely reduced. They were flat and contained few osmiophilic granules. We conclude that perinatal apoptosis is responsible for the loss of Merkel cells lacking innervation in NT3 null mice.

Animals↗

PubMed2004

Cytokeratin 20 confirms merkel cell metastasis to stomach.

Merkel cell carcinoma (MCC) is an uncommon, aggressive neuroendocrine carcinoma of the skin. Its prognosis is poor because of involvement of regional lymph nodes and metastases to distant sites such as bone, liver, lung, and brain. Very few metastases are reported to the gastrointestinal tract. Several studies have shown the utility of cytokeratin 20 to differentiate MCC from other small round blue cell tumors, particularly those with neuroendocrine differentiation. In this case report, we present an unusual metastasis to the stomach and the utility of cytokeratin 20 immunohistochemistry to confirm MCC.

Carcinoma, Merkel Cell↗

PubMed2000

Developmental origin of avian Merkel cells.

We have investigated the developmental origin and ultrastructure of avian Merkel cells by electron microscopy and chick/quail transplantation experiments. On embryonic day 3, chick leg primordia were homotopically grafted onto Japanese quail host embryo. Fourteen days later, quail cells that had migrated into grafted chick legs were identified according to the masses of heterochromatin associated with the nucleolus that are characteristic for quail. Both in chick and quail, Merkel cells are usually located in the dermis just below the epidermis. They are placed between nerve terminals either individually or in small groups wrapped in sheaths that are formed by glial cell processes. Occasionally, some Merkel cells appear in nerve fascicles and within Herbst corpuscles. Merkel cells, as well as glial cells, in grafted chicken legs were of quail origin. This finding provides evidence against the epidermal origin of avian Merkel cells and indicates that Merkel cells are derived from neural crest cells that colonise, together with glial cells and melanocytes, the developing limb primordium.

Animals↗

PubMed1995

Merkel cell carcinoma with a desmoplastic portion.

Merkel cell carcinoma of the skin usually has a trabecular, intermediate-cell or small-cell pattern of differentiation. We report the case of a 66-year-old man who developed a progressive multinodular plaque that showed a prominent desmoplastic component on preliminary biopsy. Immunohistochemical and ultrastructural studies and the final surgical specimen confirmed that the tumor was a Merkel cell carcinoma. The presence of desmoplasia may mask the diagnosis of Merkel cell carcinoma.

Aged↗

PubMed2006

Rapid growth of Merkel cell carcinoma after treatment with rituximab.

Merkel cell carcinoma is an uncommon neuroendocrine carcinoma of the skin. We report a case of rapid growth of Merkel cell carcinoma after treatment with rituximab, a new anti-CD20 monoclonal antibody, for acquired factor VIII inhibitor. We propose that rituximab may place patients at higher risk for aggressive Merkel cell carcinoma thus necessitating the need for increased long-term surveillance of these patients.

Aged↗

PubMed2003

[Significance of sentinel lymph node biopsy in Merkel cell carcinoma. Analysis of 11 cases].

BACKGROUND: Merkel cell carcinoma is an aggressive cutaneous neoplasm with a high propensity for nodal metastases. Regional lymph node involvement develops in 45 to 65 p. 100 of patients. We evaluated in Merkel cell carcinoma the use of sentinel lymph node biopsy which allows the identification of occult nodal metastases. PATIENTS AND METHODS: Eleven patients diagnosed with Merkel cell carcinoma without clinical nodal involvement underwent pre-operative lymphoscintigraphy followed by sentinel lymphadenectomy with histologic analysis. Identification of microscopic nodal metastases led to complete lymph node dissection and adjuvant radiation therapy to the lymph node basin. RESULTS: The sentinel lymph node was successfully identified in 9 patients. Two patients demonstrated metastatic disease in their sentinel lymph nodes. At subsequent complete node dissection, one of two patients had an additional metastatic lymph node. None of the eleven patients experienced recurrent disease at a follow-up varying from 1 to 42 months. One patient with a negative sentinel lymph node experienced lymphoedema. COMMENTS: Our results are consistent with the 14 published studies which totalled 93 patients with Merkel cell carcinoma and identified 29 patients (30 p. 100) with nodal involvement. Metastatic disease was identified only after immunohistochemical analysis in 20 p. 100 of these patients (n=6). Lymph node involvement appears to be a bad prognostic factor with 29.6 p. 100 of disease recurrence, as opposed to 3 p. 100 in patients with an uninvolved sentinel lymph node. Although the prognostic significance of this technique seems interesting, there is no optimal therapeutic approach to sentinel lymph node involvement.

Adult↗

PubMed1994

[Merkel cell carcinoma of the eyelid].

Merkel cell carcinoma is an infrequent but highly malignant cutaneous neoplasm. In a 73-year-old woman, a Merkel cell carcinoma of the right upper lid developed within 1 month, recurred within a month after its first removal, and metastasized to the parotid 2 months after secondary excision.

Aged↗

PubMed2003

Neural crest origin of mammalian Merkel 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.

Animals↗

PubMedDate not supplied

The Merkel cell and associated neoplasms in the eyelids and periocular region.

Merkel cells are clear oval cells in the epidermis and outer root sheaths of hair follicles, which are probably of epithelial origin, share ultrastructural features with neuroendocrine cells, and are found in association with touch receptors. In the eyelid, they occur singly in the epidermis and external root sheaths of hairs and eyelashes, and in specialized touch spots alternating with eyelashes. Their typical electron microscopical and antigenic features include dense-core granules, intranuclear rodlets, spinous processes, and a positive reaction for specific cytokeratins, epithelial membrane antigen, neuron-specific enolase, chromogranin and synaptophysin. Merkel cell carcinoma probably develops from precursor cells which give rise to keratinocytes and Merkel cells, and nearly one out of ten Merkel cell carcinomas occur in the eyelid and periocular region. They tend to be bulging lesions near the lid margin of elderly patients, reddish in color, and erythematous with telangiectatic vessels. The diagnosis is based on the frequent presence of neurofilaments and paranuclear aggregates of intermediate filaments in addition to features typical of normal Merkel cells. The tumor often mimics lymphoma or undifferentiated carcinoma and frequently invades lymphatic vessels. One third of Merkel cell carcinomas recur, almost two thirds give rise to regional node metastases, and up to one half metastasize widely and result in death. Initial treatment should be prompt and aggressive, with wide resection and routine postoperative irradiation. Although metastatic lesions often respond to radiation therapy and cytostatic drugs, these treatments are mainly of palliative value.

Carcinoma, Merkel Cell↗

PubMed2005

Combined Merkel cell carcinoma and atypical fibroxanthoma.

BACKGROUND: Although there are reports of squamous cell carcinoma arising within and adjacent to Merkel cell carcinoma, and one report of an atypical fibroxanthoma-like tumor arising in an irradiated recurrent Merkel cell carcinoma, there have previously been no reports of an immunohistochemically verified atypical fibroxanthoma occurring in conjunction with a Merkel cell carcinoma. OBJECTIVE: We report on a neoplasm with distinct features of both Merkel cell carcinoma and atypical fibroxanthoma. METHODS: Histologic and immunohistochemical evaluations were performed. RESULTS: Our results verify the finding of a combined Merkel cell carcinoma and atypical fibroxanthoma. CONCLUSION: This case is an interesting and unusual combination of tumors. The origin of the Merkel cell carcinoma is revisited. Debated origins include neuroendocrine, epithelial, and pleuripotent stem cell.

Aged↗

PubMed1981

Fine structural and morphometric studies of the Merkel cell during fetal and postnatal development.

The morphological and morphometric changes of the Merkel cells during fetal and postnatal development were studied in the glabrous digital pads of rats. In 20-day-old fetus rats, the Merkel cells we observed were present in the lower spinous and basal layers, and not associated with axon terminals. The Merkel cell granules were few and sparse. The Merkel cell had clumps of fibrils and formed many desmosomes with surrounding keratinocytes. In postnatal rats, innervation was followed by an increase in the number of Merkel cell granules, and their specific accumulation. The fibrils of the Merkel cells were not prominent. It was found by t-test that the numerical density of the Merkel cell granules significantly increased from the fetal stage to 4-day-old postnatal rats. These results suggest that the Merkel cells are present in the epidermis without nerve contact in 20-day-old fetus rats, and that innervation is necessary for the increase of cellular activity in Merkel cells.

Age Factors↗

PubMed1982

Migration of Merkel cells in the labial mucous epithelium of adult rabbits following mental nerve resection.

Merkel cells in the lower labial mucosa of adult rabbits were studied electron microscopically, 9, 21, 28, and 50 days after resection of the mental nerves. By day 9, nerve fibers were completely retracted from the epithelial layer of the mucosa. On and after day 21, Merkel cells were located not only in the basal layer but also in the prickle or more superficial cell layers. The ultrastructure of the migrating Merkel cells was unchanged, both as to the amount and location of the specific cored granules in the cytoplasm, until the cells reached the granular cell layer. The position of the migrating Merkel cells differed from cell to cell, and migration continued for at least 50 days. A remarkably large number of immature Merkel cells was observed in the basal and suprabasal cell layers of the denervated epithelium even by day 50. Therefore, the possibility of the reproduction of Merkel cells exists. The migrating Merkel cells, as well as the keratinocytes in the same cell layer, had degenerated drastically in the parakeratinized cell layer. This seems to indicate that the Merkel cells belong to the line of keratinocytes.

Animals↗