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Serotonin-like immunoreactivity in Merkel cells and their afferent neurons in touch domes from the hairy skin of rats.

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THE ANATOMICAL RECORD 232:112-120 (1992)
Serotonin-Like lmmunoreactivity in Merkel Cells and Their Afferent
Neurons in Touch Domes From the Hairy Skin of Rats
KATHLEEN B. ENGLISH, ZU,O-ZHONG WANG, NAIDA STAYNER,
LARRY J. STENSAAS, HERVE MARTIN, AND ROBERT P. TUCKETT
Department of Physiology, University of Utah School of Medicine, Salt Lake City, Utah
ABSTRACT
Immunoreactivity to serotonin was observed in Merkel cells as
well as the afferent type I nerves terminating upon them in touch domes excised
from the belly skin of rats. Type I nerves were strongly immunoreactive and could
be traced through the dermis of the domal papilla. Merkel cell immunoreactivity
was sometimes seen in the entire cell, but was often localized in the Merkel cell
cytoplasm adjacent to nerve terminals and may have been in the terminals themselves. Domes were fixed by immersion in 4% paraformaldehyde-lysine-sodiumm-periodate (PLP) fixative at 4°C for 2.5-3 hours and cryoprotected in 30% sucrose
overnight. Sections were processed with the avidin-biotin complex peroxidase
(ABC), peroxidase-antiperoxidase(PAP), and indirect immunofluorescence techniques with rabbit antiserum generated against serotonin.
Merkel cells are situated in the basal epidermis of
the most tactually sensitive regions of vertebrate skin.
They are found in fish (Lane and Whitear, 1977), amphibians (Crowe and Whitear, 1978) and mammals, including humans (Merkel, 1875; Smith, 1970). Their
presence in so many classes implies they offer a selective advantage in those animals possessing them
(Simon and Hiller, 19891,but just what that role is has
yet to be verified.
In the hairy skin of rats, Merkel cells have a high
density in the upper cylindrical cuff of the external root
sheath of vibrissae. They are also in the basal epidermis of touch domes located on trunk skin or the whisker pad (Nurse et al., 1983; Nurse and Diamond, 1984).
Following depilation, domes are visible as small elevations (170-314 pm in diameter; English, 1977; Leon
and McComas, 1984) rising above the skin surface. On
the trunk of adult rats, they are spaced about 3-5 mm
apart and are associated with large tylotrich hairs
(Straile, 1960).
Almost all Merkel cells are innervated (Pasche et al.,
1990). A type I afferent fiber forms a discoid shaped
terminal on the dermal side of a Merkel cell’s surface
(Iggo and Muir, 1969; English et al., 1980). Merkel
cells characteristically contain dense cored granules
-100 nm in diameter that are polarized next to the
nerve terminals (Fig. 1).Sometimes granules fuse at
synapse-like junctions (Chen et al., 1973). Mechanical
depression of touch domes elicits a n irregular, slowly
adapting discharge in the afferent type I fibers (Iggo
and Muir, 1969).
There is physiological evidence in support of two conflicting hypotheses: either Merkel cells transduce mechanical energy into nerve impulses (Horch e t al.,
1974; Findlater et al., 1987), or type I nerve endings
are the true receptors (Diamond et al., 1988; Gottschaldt and Vahle-Hinz, 1981). In addition, Merkel
cells have been proposed to be the following: (1)paracrine regulators of the epidermis (Moll et al., 1986), (2)
targets for growing nerves (Scott et al., 1981; Diamond,
0 1992 WILEY-LISS, INC.
1982; Yasargil et al., 1988), (3) neuromodulators of the
nerve terminal’s mechanosensitivity, or (4) developmental “positional labelers” for the central nervous
system (Diamond et al., 1988).For any of these functions, the contents of the dense cored granules and the
stimuli causing their release are likely to be of central
importance.
Because serotonin has previously been shown to excite type I cutaneous afferent neurons in vivo (Beck
and Handwerker, 1974), the present immunohistochemical study was conducted to determine if i t might
be found in Merkel cell-axonal complexes. If present,
serotonin’s role as a neurotransmitter in this system
could be tested in a recently modified in vitro skin
preparation (Reeh, 1986).
MATERIALS AND METHODS
Adult Sprague Dawley rats of both sexes were anesthetized with a n intramuscular injection of ketamine
hydrochloride (100 mgiml) mixed with acepromazine
(10 mg/ml) at 10 parts to 1, followed by 4% chloral
hydrate administered subcutaneously according to
body weight. Because of their large size, domes were
removed from the belly after the fur was clipped and
depilated (Nair).
The tissue was (1) immersed into ice-cold, freshly
prepared 4% paraformaldehyde-lysine-sodium-m-peroidate (PLP) fixative in 0.1 M phosphate-buffered saline
(PBS; pH 7.4) for 2.5-3 hours; (2) rinsed in PBS for 10
minutes, followed by 15% sucrose in PBS for 1 hour;
and (3) left in 30% sucrose in PBS overnight at 4°C.
Individual domes were oriented on their side for sectioning, snap frozen in OCT, sectioned at 5-10 km, and
Received March 22, 1991; accepted May 10, 1991.
Address reprint requests to Kathleen B. English, Ph.D., Department of Physiology, University of Utah School of Medicine, 410 Chipeta Way, Research Park, Salt Lake City, UT 84108.
SEROTONIN I N MERKEL CELLS AND AFFERENT NERVES
113
Fig. 1. Electron micrograph of a Merkel cell (MI and its associated
type I nerve terminal (NT) with numerous mitochondria. The touch
dome was excised from an adult rat. The Merkel cell has dense cored
granules (g) in its cytoplasm. Spine-like processes (*) extend among
neighboring keratinocytes of the epidermis. Merkel cells are above
the epidermal basement lamina (bl) and form desmosomes (d) with
the keratinocytes. Scale bar = 0.5 pm.
mounted on chrome alum-subbed slides. The tissue was
processed for immunocytochemical staining using conventional peroxidase-antiperoxidase PAP (Sternberger, 1986), avidin-biotin complex peroxidase ABC (Hsu
et al., 1981), and indirect immunofluorescence techniques (Coons, 1958).
Sections were stained with rabbit primary antiserum
to serotonin [1:5,000 (NT102 [lyophilizedl; Eugene Tek
Int.) or 1:200-300 (AB125; Chemicon)] overnight a t
4°C. Blocking serum was 10% normal goat serum in 0.1
M PBS saline. All antibodies were diluted in 0.1 M PBS
saline plus 1% normal goat serum and 1%crystalline
grade bovine serum albumin (Sigma, A7638). A 10minute wash in 3% H,02 quenched endogenous peroxidase activity in the skin. Biotin in sebaceous glands
was bound up with a n avidin-biotin blocking step
(Vector).
For the ABC and PAP techniques, the secondary
antisera were biotinylated goat anti-rabbit (1:400; Vector) or goat antiserum to rabbit (1:lOO).The PAP complex was prediluted (Dakopatts). The reaction products
were visualized by the diaminobenzidine (DAB) reaction, which was closely monitored under a brightfield
microscope. DAB was freshly filtered and prepared
each run using 10 mg DAB (Sigma), 20 mls 0.1 M PBS,
pH 7.4, and 4 ~1 30% HzOz (Sigma). The secondary
antiserum for indirect immunofluorescence was goat
anti-rabbit IgG-L-Rhodamine [(1:200-1:400) Boehringer Manheiml.
The specificity of the serotonin antiserum was
checked by preabsorbing serotonin antiserum at working dilution with 5-HT bound to agarose (Sigma,
H7136) or with serotonin creatinine sulfate (Sigma).
Other controls consisted of inclusion of 2 mg/ml of polyL-lysine (Sigma #P0879) in the antiserum diluent
(Scopsi et al., 19861, omission of the primary or secondary antiserum, or substituting primary antiserum with
normal, nonimmune rabbit serum (Eugene Tek Int.).
Rat carotid body served a s positive control tissue.
RESULTS
Serotonin-like immunoreactivity was observed in
Merkel cells, in afferent type I neurons with Merkel
cells (Fig. 2) and in dermal mast cells. Immunoreactivity in Merkel cells was often strongest in their cytoplasm adjacent to nerve terminals or in the terminals
themselves (Figs. 3A, 4A). The reaction time for immunostaining to occur was approximately 2-5 min. Not
every Merkel cell in a given section was immunoreactive, but roughly 25% were. Type I neurons were
strongly immunoreactive (Figs. 2B, 4B,C). Immunostaining was identical for both antisera tested (NT102
114
K.B. ENGLISH ET AL.
Fig. 2. A Arrows point to Merkel cells immunoreactive to serotonin
in the basal epidermis of a touch dome from a n adult rat. ABC immunoperoxidase technique, interference contrast microscopy. Scale
bar = 10.0 pm. B: Arrows point to Merkel cells in the epidermis, and
the open arrow points to the type I nerve in the dermis of a touch
dome. Both are imrnunoreactive to serotonin. ABC irnmunoperoxidase technique, interference microscopy. Scale bar = 10.0 pm.
Fig. 3. A Section of a touch dome with Merkel cells (arrows) and
their nerve terminals immunofluorescently labeled against serotonin. Scale bar = 10.0 km. B: Control section of a touch dome where
normal rabbit serum was substituted for the primary antiserum. Sections receiving preabsorbed antiserum were identical in appearance.
Scale bar = 10.0 pm.
116
K.R. ENGLISH E T AL.
Fig. 4. A Touch dome from an adult rat. Arrows point to type I
nerve terminals immunofluorescently labeled for serotonin. Scale bar
= 10.0 pm. B,C: Open arrows point to immunofluorescent type I
nerves labeled for serotonin. The nerves rise in the dermis and terminate upon Merkel cells (arrow) in the basal epidermis of touch
domes. Scale bar = 10.0 pm.
SEROTONIN IN MERKEL CELLS AND AFFERENT NERVES
Ilyophilizedl Eugene Tek Int. and AB125 Chemicon).
Glomus cells of the carotid body were immunoreactive
for serotonin (Gronblad et al., 1983) and thus substantiated the specificity of the antisera tested.
Control sections incubated without primary or secondary antisera failed to demonstrate any immunoreactivity, as did sections incubated with normal rabbit
serum or antiserum preabsorbed with bound serotonin
(Fig. 3B). Preabsorption with serotonin creatinine sulfate required 10-1M concentrations for immunostaining to be eliminated and was not reliably reproducible
(perhaps because the antiserum was generated against
serotonin in its conjugated form). Inclusion of po1y-Llysine in the antiserum diluent did not abolish staining
in the Merkel cells or the type I nerves, indicating the
immunoreaction was not due to nonspecific binding of
basic peptides.
DISCUSSION
In the present investigation, serotonin-like immunoreactivity was found in Merkel cells and their afferent nerves in touch domes excised from the hairy skin
of rats. This supports previous immunohistological
studies demonstrating serotonin in Merkel cells from
the eel (Zaccone, 1986) and pig (Garcia-Caballero et al.,
1989b), as well as studies employing permanganate
staining and reserpine treatment to demonstrate
monoamines in Merkel cell granules of mice (Chao and
Liang, 1975). However, it is a t variance with other less
sensitive and selective histochemical and pharmacological investigations in cats and rats (Smith and
Creech, 1967; Iggo and Muir, 1969; Hartschuh and
Grube, 1979; see also Diamond et al., 1986).
In rats, Merkel cells have been shown to contain the
opioid peptide metenkephalin (Hartschuh e t al., 1979)
and the putative neurotransmitter adenosine triphosphate (ATP; Crowe and Whitear, 1978; Nurse et al.,
1983). In various other species, Merkel cells have been
demonstrated to be immunoreactive for neuron specific
enolase, chromogranin A, vasoactive intestinal polypeptide (VIP), substance P, pancreastatin, and calcitonin gene-related peptide (Alvarez et al., 1988; Gu et
al., 1981; Hartschuh and Weihe, 1988, 1989).
It is common for biogenic amines to be colocalized
with transmitters and neuropeptides in excitatory or
receptosecretory cells (Gauweiler et al., 1988; Kanagawa et al., 1986; Forloni et al., 1987). Indeed by definition, cells of the APUD (amine precursor uptake and
decarboxylation), DNES (diffuse neuroendocrine system), or paraneuron class characteristically possess
amines and peptides as well a s marker molecules such
as neuron specific enolase and chromogranin A (Fujita,
1983; Pearse, 1986; Hartschuh and Weihe, 1988).
In general, Merkel cells of the skin, along with chromaffin cells of the adrenal medulla, neuroepithelial
cells of the lung, enterochromaffin cells of the gastrointestinal tract, and glomus cells of the carotid body
are all considered to be neuroendocrine cells, belonging
to the APUD, DNEs, paraneuron, or receptosecretory
class of cells. The presence of biogenic amines in Merkel cells might therefore be expected, but it is not a n
absolute requirement for the receptosecretory classification to stand.
The present study expands the number of species in
which serotonin has been found in Merkel cells. As
117
methodologies are refined, there may be more correlation between immunohistochemical profiles of Merkel
cells (see Table 1).For instance, met-enkephalin was
originally reported to only occur in Merkel cells from
rodents (guinea pigs, mice, and hamsters), but not in
those from cats, dogs, pigs, and humans, which demonstrated immunoreactivity to vasoactive intestinal polypeptide (VIP) instead (Hartschuh et al., 1984). Yet a t
the same time other investigators found met-enkephalin immunoreactivity in Merkel cells from primates
(Warner e t al., 1983). Unfortunately, there are technological difficulties with immunohistochemical staining. This is exemplified by synaptophysin reactivity
only occurring in perfusion-fixed guinea pig tissue and
not in immersion-fixed pig and human skin. Similarly,
chromogranin A is shown with bovine-generated antiserum rather than porcine-generated antiserum
(Hartschuh and Weihe, 1988).
The existence of serotonin-like immunoreactivity
both in Merkel cells and their afferent nerves in the
present study was unexpected. It was found in Merkel
cells but not afferent nerve fibers in the pig and eel
(Zaccone, 1986; Garcia-Caballero et al., 198913). However, similar observations have been made in other
APUD cells and their sensory nerve supply. For example, in the adrenal medulla, both adrenaline cells and
their afferent neurons express immunoreactivity for
enkephalins (Schultzberg et al., 1978; Pelto-Huikko et
al., 1985). Similarly, catecholaminergic primary sensory neurons terminate upon catecholamine-containing type I glomus cells in the carotid body (Katz and
Black, 1986). The physiological significance of dual localization of putative neurotransmitter substances in
APUD cells and their afferent neurons is presently unknown.
Earlier enzymatic histochemical studies of the type I
nerve endings of Merkel cells indicated acetylcholinesterase and leucine aminopeptidase were present
in rabbits, and alkaline phosphatase in cats and guinea
pigs (Winkelmann, 1977). The present investigation is
the first study showing a specific immunohistochemical reaction in the type I nerve terminals on Merkel
cells. Other investigators have found CGRP immunoreactive nerve fibers occasionally associated with Merkel cells in the footpad of rats, but these were not the
type I fibers of the Merkel cell-axonal complex (IshidaYamamoto et al., 1989).
Serotonin is known to be ultrastructurally associated
with synaptic vesicles (Sanders-Bush and Martin,
1982). Merkel cells have numerous dense cored granules, but their afferent neurons do not. There is, however, considerable experimental evidence that a large
proportion of serotonin is stored in a cytoplasmic extravesicular form (Halaris and Freedman, 1977; Lewis
and Moertel, 1978; Sanders-Bush and Martin, 1982).
Therefore, the sparcity of dense-cored granules in the
afferent nerves terminating upon Merkel cells does not
exclude the possibility of serotonin being present in
cytoplasmic stores.
The role that serotonin plays in the Merkel cell-axonal complex remains to be determined. It may be involved in any one of several biological processes. For
example, serotonin may be important in the generation
of type I responses in afferent nerves because both serotonin formation and type I response are highly de-
118
K.B. ENGLISH ET AL.
TABLE 1. Merkel cell immunohistochemistry
Substance
Met-enkephalin
Substance P
CGRP (calcitonin gene-related peptide)
VIP
PHYPMI (peptide histidine isoleucine)
Pancreastatin
Serotonin
Bombesin
NSE (neuron specific enolase)
Cytokeratin 8,18
PGP (protein gene product 9.5)
Synaptophysin
Species
rat
guinea pig, mouse, hamster
monkey
adult and fetal pig
adult cat, adult mouse, adult pig
adult and fetal pig
adult pig, adult cat, adult mouse
adult cat
adult pig
dog, cat, human, pig
adult cat, mouse, pig
adult pig
adult cat, mouse, pig
adult and fetal pig
adult human and pig
eel
Plg
fetal human
eel
cat, rat
adult and fetal human
adult human
rabbit, pig, human
human
human
Pig
human, rabbit, pig
adult guinea pig
adult and fetal pig
adult cat, adult pig
adult and fetal pig
Chromogranin A
s-100
pendent upon POz. Type I receptors fail to respond to
mechanical stimulation in a n oxygen-depleted environment. Furthermore, Merkel cells become degranulated
when touch domes are mechanically stimulated under
hypoxic conditions (Findlater et al., 1987). On the other
hand, serotonin may be required for synthesis and storage of polypeptides (Owman e t al., 1973). Alternatively, recent research indicates bidirectional communication exists between neuroendocrine cells and the
immune system, wherein serotonergic systems inhibit
immune responses (Warren e t al., 1990; Devoino et al.,
1990). Now that serotonin has been identified in the
Merkel cell-axon complex, its function will be the focus
of future electrophysiological and neuropharmacoligical investigations.
ACKNOWLEDGMENTS
The authors wish to express thanks to Dr. Andy
Towles of ETI, Dr. P. Burgess for his critique of the
manusmirk. and to Vicki Skelton for twine: the manuscript. Supported by NIH grants" -NS%7938 and
NS26229.
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analysis of calcitonin gene-related peptide and vasoactive intestinal polypeptide in Merkel cells and cutaneous free nerve endings of cats. Cell Tissue Res. 254r429-437.
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like, touch, merkel, serotonin, skin, neurons, dome, afferent, immunoreactivity, rats, hair, cells
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