Dynamics of Merkel Cell Patterns in Developing Hair Follicles in the Dorsal Skin of Mice, Demonstrated by a Monoclonal Antibody to Mouse Keratin 8

Abstract

In order to explore the origin and significance of Merkel cells in the hairy skin of mammals, the development of Merkel cells and nerve endings in the dorsolateral skin of C57BL mouse embryos was studied in serial cryostat sections. At 13 and 14 days of gestation, application of a monoclonal antibody to mouse keratin 8 (mK8) resulted in specific immunofluorescence of all cells in the epidermis and periderm. The periderm retained specific staining until it was shed, around 18 days. At 15 days, mK8-specific staining elsewhere was restricted to scattered immature Merkel cells in the developing tylotrich follicles and the adjacent epidermis. Between 16 and 17 days, these cells assembled within the basal epidermal layer, caudal to each tylotrich follicle, to form a disc-shaped rudiment of a ‘haarscheibe’ or touch dome. No Merkel cells were found in association with the later developing awl and zigzag follicles. In mice homozygous or hemizygous for the Tabby mutation, in which tylotrich follicles never form, no Merkel cells were found in any part of the dorsolateral skin. In mice homozygous for the recessive downy mutation, in which all three types of hair are present but reduced in size, Merkel cell development was the same as in wild-type mice. Nerve endings were located in the upper dermal mesenchyme by a monoclonal antibody to neural cell adhesion molecule. This antibody also stained plasma membranes in specific parts of the hair follicles during their development. From 14 to 19 days, none of the nerve endings were seen in contact with the epidermis or the follicle epithelium, even in areas where Merkel cells were located. These findings support the view that both location and early differentiation of Merkel cells in the dorsolateral epidermis are independent of neural influences but linked to the development of tylotrich follicles.

Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis

“…These results might also explain why it has been previously reported that MCs originate from NCCs (Szeder et al, 2003). With the currently available tools and these mouse models, all evidence points to MCs being derived from epidermal cells, as has been previously suggested (Moll et al, 1986(Moll et al, , 1990Narisawa and Hashimoto, 1991;Moll and Moll, 1992;Cheng Chew and Leung, 1994;Vielkind et al, 1995), although a minor contribution of NCCs to MCs of the whisker region could not be entirely ruled out.…”

“…Further evidence against the neural crest origin of MCs is their temporal appearance. MCs are present in the epidermis before the appearance of other neural crest derivatives such as nerve endings of the skin (Narisawa and Hashimoto, 1991;Cheng Chew and Leung, 1994;Vielkind et al, 1995). In humans, MCs are identifiable and transplantable several weeks before nerves reach the fetal epidermis (Moll et al, 1986(Moll et al, , 1990Moll and Moll, 1992), suggesting that MCs do not originate from NCCs.…”

“…Using antibodies that specifically recognize MCs (Kim and Holbrook, 1995;Moll et al, 1995;Vielkind et al, 1995), MCs were first detected in the whisker region around embryonic day (E) 15, whereas in the back skin and in the paw epidermis, MCs were detected at E17 ( Fig. 1 A and Fig.…”

“…The cells coexpressing K14 and MC markers during embryonic development may be the previously described transitional cells seen by electron microscopy, which were thought to represent the transition from epidermal cells to MCs (Tachibana and Nawa, 1980). Furthermore, the demonstration that early specified MCs coexpress P-cadherin, a marker of embryonic hair follicle (HF) progenitors (Rhee et al, 2006), and the absence of MC specification in Tabby mutant mice (Vielkind et al, 1995), which present defects in HF morphogenesis, suggest that HF progenitors and MC specification could be tightly linked.…”

Responses of hair follicle–associated structures to loss of planar cell polarity signaling

“…In mice, follicles and follicle-associated structures form on different schedules. Guard hair follicles and semicircular Merkel cell clusters are present by embryonic day (E) 16, and follicle-associated lanceolate nerve endings are present by postnatal day (P)0, but sebaceous glands and APMs develop postnatally (2,(10)(11)(12)(13).…”