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Distribution of GAP-43 nerve fibers in the skin of the adult human hand.

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THE ANATOMICAL RECORD PART A 272A:467– 473 (2003)
Distribution of GAP-43 Nerve Fibers
in the Skin of the Adult Human Hand
LAURA VERZÉ,1* VIGLIETTI-PANZICA CARLA,1 STELLA MAURIZO,2
SICA MONICA,1 AND PANZICA GIANCARLO1
1
Department of Anatomy, Pharmacology, and Forensic Medicine, Laboratory of
Neuroendocrinology, University of Torino, Torino, Italy
2
Plastic Surgery Division and Burn Unit, CTO-CRF, Maria Adelaide Hospital,
Torino, Italy
ABSTRACT
Skin is an important region of somatic sensory input, and is one of the
most innervated areas of the human body. In this study, we investigated in
human hand skin the distribution of nervous structures immunoreactive for
the growth-associated protein 43 (GAP-43) and the protein gene product 9.5
(PGP 9.5). GAP-43 is a neuronal presynaptic membrane protein that is
generally considered to be a marker of neuronal plasticity. PGP 9.5 is a
neuron-specific soluble protein that is widely used as general marker for the
peripheral nervous system. The entire neural network of the dermis and
epidermis was stained with antibody to PGP 9.5. In the dermis, there were
fewer GAP-43-immunostained nerve fibers than PGP 9.5-immunostained
nerve fibers, whereas in the epidermis the numbers were equal. Only some
Merkel cells and Meissner corpuscles were GAP-43-immunoreactive. In
conclusion, our results show that GAP-43 protein is expressed in a subset of
PGP 9.5-immunoreactive nerve structures. Anat Rec Part A 272A:467– 473,
2003. © 2003 Wiley-Liss, Inc.
Key words: hand skin; innervation; growth-associated protein
43; human
Growth-associated protein (GAP-43) is a membrane protein that is expressed at high levels during neural development, and is newly produced in injured and regenerating adult nerve tissue. It is considered to be a marker for
sprouting, and is usually associated with physiological
events such as neuronal growth and synaptic plasticity
(Benowitz and Routtenberg, 1987; Skene, 1989; Hoffman,
1989; Gispen et al., 1991). In the adult central nervous
system, GAP-43 is present in several types of neurons and
in regions of intense synaptic remodeling (Benowitz et al.,
1988, 1990). In the normal adult peripheral nervous system, it is expressed at low levels in motor neuron axons
(rat: Li and Dahlstrom, 1993), but is highly expressed in
sensory nerve fibers (human: Fantini and Johansson,
1992; rat: Verzé et al., 1999). GAP-43-immunoreactivity
has also been demonstrated in adult mammalian ganglionic neurons. In the rat it is extensively expressed in the
autonomic nervous system (Stewart et al., 1992), whereas
in humans it has been demonstrated in trigeminal primary sensory neurons (Del Fiacco et al., 1994). GAP-43
mRNA is expressed in the preganglionic sympathetic neurons of the rat spinal cord (Michael and Priestley, 1995),
©
2003 WILEY-LISS, INC.
and in prevertebral and paravertebral human ganglia
(Schmidt et al., 1991).
Axon regeneration following peripheral nerve injury is
characterized by a rapid increase of GAP-43 expression in
sensory dorsal root ganglia (Sommervaille et al., 1991;
Wiese et al., 1992) and in motor neurons (Palacios et al.,
1994). After nerve injury, GAP-43 is transported to both
the peripheral and central nerve endings of sensory neurons, and may be involved in their peripheral regeneration
Grant sponsor: Fondazione Piemontese Studi e Ricerche sulle
Ustioni (FPSRU).
*Correspondence to: Dr. Laura Verzé, Department of Anatomy,
Pharmacology, and Forensic Medicine, Laboratory of Neuroendocrinology, University of Torino, corso Massimo D’Azeglio 52-I10126, Torino, Italy. Fax: ⫹39-011-6707732.
E-mail: laura.verze@unito.it
Received 11 June 2002; Accepted 23 January 2003
DOI 10.1002/ar.a.10056
468
VERZÉ ET AL.
and central reorganization (Woolf et al., 1990, 1992). Loss
of the connections of sensory neurons with their peripheral target tissues after nerve transection or crushing is
considered to be one of the triggers for induction of
GAP-43 expression. Environmental or target-derived factors, as well as their interactions, may regulate GAP-43
expression (Oestreicher et al., 1997).
Skin is an ideal model for studying neurochemical
markers in the peripheral sensory and autonomic nervous
system of adult humans. However, little has been published concerning GAP-43 immunoreactivity in humans
(Fantini and Johansson, 1992; McArthur et al., 1998;
Kinkelin et al., 2000; Verzé et al., 2000). Immunoreactivity patterns for both GAP-43 and PGP 9.5 have been
reported for human skin, but a complete study of the
innervation in the human hand has yet to be performed.
GAP-43 distribution has been compared with expression
of a neuron-specific marker, the protein gene product 9.5
(PGP 9.5), which is one of the most widely distributed
markers of the peripheral nervous system (Gulbenkian et
al., 1987; Dalsgaard et al., 1989; Ramieri et al., 1990,
1992a, b; Wang et al., 1990). The aim of the present study
was to describe the distribution of GAP-43 and PGP 9.5
immunoreactivity in the skin of the human hand, a highly
innervated area.
MATERIALS AND METHODS
Fixation and Immunocytochemistry
Samples of normal hand skin of 10 adults (six males and
four females, 20 – 40 years old) were removed during reconstructive procedures, after informed consent was obtained. Three samples were taken from each subject. The
specimens (1.5 cm ⫻ 1 cm) were taken from the dorsal (two
subjects) and ventral (eight subjects) areas of the hand. Of
the latter, three were biopsed in the thumb, three in the
palm, and two in the index finger.
The specimens were immediately immersed in Zamboni’s solution (4% paraformaldehyde and 0.2% picric acid in
0.01 M phosphate-buffered saline (PBS), pH 7.2–7.4) and
fixed overnight at 4°C. They were washed in PBS containing 15% sucrose for 3 days at 4°C, and then frozen.
Serial 20-␮m-thick sections were cut with a cryostat
(Microm, Heidelberg, Germany) and collected on chromealum gelatinized slides for the immunohistochemical procedure. Endogenous peroxidase activity was inhibited by
washing the sections in methanol/hydrogen peroxide
(Streefkerk, 1972) and incubating them in normal serum
(30 min, 15 ␮l/ml PBS) to prevent nonspecific staining.
Adjacent sections were then incubated overnight at room
temperature with polyclonal primary antiserum diluted in
PBS containing 0.25% Triton X-100, 1:6000 anti-GAP 43
(donated by L. Schrama, Utrecht, The Netherlands; for
details of the antibody, see Oestreicher et al. (1983) and
1:8000 anti-PGP 9.5 (Ultraclone, Isle of Man, UK). After
the sections were washed briefly, they were incubated for
60 min in a secondary biotinylated antibody, and then in
an avidin-biotinylated peroxidase complex (Vectastain
Elite Labtec; Vector, Burlingame, CA) for 60 min at room
temperature. Peroxidase activity was visualized with a
solution containing 0.20 mg/ml 3,3⬘-diaminobenzidine
(DAB; Sigma, St. Louis, MO) in 0.05 M Tris-HCl buffer,
pH 7.6, as chromogen and 0.35% hydrogen peroxide. The
reaction was blocked by rinsing the sections in distilled
water. Alcohol-dehydrated sections were then coverslipped with Entellan (Merk, Milano, Italy). To improve
the identification of positive structures, some sections
were counterstained with 1% toluidine blue. Control reactions were performed by replacing the primary antibody
with normal serum. The specificity of the antibodies for
human tissues had been verified in earlier studies (Doran
et al., 1983; Benowitz et al., 1989).
Photographic Recording
Specimens were observed with a bright-field microscope
(Diaplan; Leitz, Wetzlar, Germany) equipped with a
Kodak Wratten no. 75 filter to enhance DAB product visibility.
To increase the number of in-focus structures, we used
image reconstruction based on several images of the same
field digitized at different focal planes. The reconstruction
was performed using NIH-IMAGE 1.61 software (National
Institutes of Health, Bethesda, MD) according to the
method of Verzé et al. (1999). The resulting images were
then sharpened, contrast-enhanced, and stored for printing with Adobe Photoshop 5.1.
Quantification
The frequency of PGP 9.5- and GAP-43-immunoreactive
(-ir) structures was evaluated in five sections for each
specimen. We applied a semiquantitative method, with
scores expressed as ⫹⫹⫹ ⫽ high frequency; ⫹⫹ ⫽ medium frequency; ⫹ ⫽ low frequency; and –⫽ absence.
RESULTS
All of the nerve fibers were PGP 9.5-ir. GAP-43-ir was
observed in the branches of nerves in the inner layers of
the dermis, from which several nerve fibers entered the
dermal plexus. Moreover, finer unmyelinated fibers ran
toward the skin surface and branched further into a subepithelial plexus. From this network thin immunoreactive
fibers reached the epidermal layers, where they ended as
free fibers and occasionally as fibers associated with immunopositive GAP-43-ir Merkel cells. Free nerve endings
were observed at all levels of the dermis, where other
anatomical structures that received sensory or autonomic
innervation were found. In particular, the sweat glands,
hair follicles, and blood vessels were surrounded by GAP43-ir nerve fibers. The distribution of GAP-43-ir nerve
fibers in comparison with the distribution of PGP 9.5-ir
elements is summarized in Table 1.
Epidermis
In the epidermis, GAP-43-ir nerve fibers were widely
distributed in the basal, spinosum, and granulosum layers, and their density was comparable to that of PGP 9.5-ir
elements (Fig. 1a– d; Table 1). GAP-43-ir nerve fibers were
most frequent in the basal layer of the epidermis, where
they appeared thin and probably unmyelinated, and they
ran among keratinocytes up to the stratum lucidum.
These fibers were in tight contact with the keratinocytes
of the basal layer of the epidermis, which they sometimes
encircled (Figs. 1c and 2e). In the basal area of the epidermis, isolated Merkel cells were GAP-43-positive. They
were present only in the hairy skin of the back of the hand
(Fig. 2c, Table 1). PGP 9.5-ir Merkel cells were present in
all specimens (Fig. 2b and d, Table 1). No nerve fibers or
endings were observed in the stratum corneum.
469
GAP-43 NERVE FIBERS IN HUMAN HAND SKIN
TABLE 1. Semi-quantitative analysis of GAP-43 and PGP 9.5 immunopositivity in the skin of the human hand
GAP-43
Ventralis
Index (2)
Thumb (3)
Palm (3)
Dorsalis
Hairy skin (2)
PGP 9.5
Ventralis
Index
Thumb
Palm
Dorsalis
Hairy skin
Epidermis
Merkel
Dermis
Meissner
Vessels
Sweat glands
Hairs
⫹⫹
⫹
⫹⫹
–
–
–
⫹⫹
⫹⫹
⫹⫹
⫹
⫹
⫹
⫹⫹
⫹⫹
⫹⫹
⫹⫹
⫹
⫹⫹
–
–
–
⫹⫹⫹
⫹
⫹⫹
–
⫹⫹
–
⫹⫹⫹
⫹⫹
⫹
⫹⫹
⫹
⫹
⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹
⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹⫹⫹
⫹
⫹⫹⫹
–
–
–
⫹⫹⫹
⫹
⫹⫹⫹
–
⫹⫹⫹
–
⫹⫹⫹
⫹⫹⫹, high frequency; ⫹⫹, medium frequency; ⫹, low frequency; –, absence of immunoreactive structures.
Fig. 1. Palmar area of hand: nerve fibers within the skin immunostained for (a) GAP-43 and (b) PGP 9.5. Note intense immunostaining in
some fibers of the dermis (short arrows) and deeper dermis (short
arrows), and in thinner nerve fibers running into the epidermis (asterisk).
Higher magnification of (c) GAP-43-ir and (d) PGP-9.5-ir nerve fibers
(asterisk) in the epidermis and subepidermal plexus (short arrows). D,
dermis; E, epidermis. Bars: (a and b) 50 ␮m; (c and d) 100 ␮m.
Dermis
the deeper layers. Both types of fiber were GAP-43-immunopositive (Fig. 2a and b, Table 1). A complex of nerve
fibers supplied the hair follicles, and all components were
immunoreactive to both GAP-43 and PGP 9.5 (Fig. 2g and
h, Table 1). GAP-43-ir nerve fibers of small diameter were
evident around the sweat glands and near the vessel walls
(Fig. 2f). However, a more restricted pattern was observed
for GAP-43 than for PGP 9.5 (Table 1). Meissner corpuscles were occasionally GAP-43-immunostained only in the
In both hairy and hairless skin, numerous GAP-43-ir
fibers were arranged in a subepithelial plexus. Most of the
positive fibers ran parallel to the skin; others crossed the
dermo-epidermal junction, entered the epidermis, and
gave rise to epidermal free endings (Figs. 1a and c, and
2e). Within the dermis, thinner tortuous, probably unmyelinated fibers terminated in this region as free endings.
Thicker probably myelinated fibers were more frequent in
470
VERZÉ ET AL.
Fig. 2. Thumb, ventral side: immunostained nerve fibers for (a)
GAP-43 and (b) PGP 9.5 in the epidermis (asterisk) and dermis (short
arrows). b: PGP 9.5-ir Merkel cells in the basal layer of the epidermis (thin
arrows), and positive fibers in the dermis (short arrows). (c) GAP-43-ir
and (d) PGP 9.5-ir Merkel cells in the basal layer of the epidermis (thin
arrows). e: Anterior area of the index finger: intraepithelial GAP-43-
positive fibers (asterisk). f: Palm: distribution of GAP-43-ir nerve trunks
(short arrows) and GAP-43:-ir nerve fibers around blood vessels and
sweat glands, in the deeper dermis (thin arrows). Hairy skin (dorsal area
of index finger): (g) GAP 43 and (h) PGP 9.5 thin nerve fibers innervating
hair follicles (thin arrows). Bars: (a– d, f, and g) 50 ␮m, and (e) 100 ␮m.
GAP-43 NERVE FIBERS IN HUMAN HAND SKIN
471
Fig. 3. Index finger, ventral side: adjacent sections
of a dermal papilla. (a) GAP-43 and (b) PGP 9.5 immunostaining of a Meissner corpuscle (asterisk) and
its axon (short arrow). Bar: 50 ␮m.
dermis of the ventral area of the index finger, whereas
they were normally positive for PGP 9.5 in the dermal
papillae of the anterior regions of the index finger, thumb,
and palm (Fig. 3a and b, Table 1).
Gender and Age
No gender-based differences in GAP-43 and PGP 9.5
expression or fiber distribution were observed in our samples.
DISCUSSION
The innervation of human skin has traditionally been
considered to consist of a plexus of fibers in the reticular
dermis and a more superficial plexus in the papillary
dermis, with most sensory endings located in the subpapillary dermis. Intraepidermal nerve terminals have been
identified in the basal layers of the epidermis that are
mainly associated with Merkel cells.
The use of the general neuronal marker PGP 9.5 has
enabled easy recognition of intraepidermal fibers by immunocytochemical staining (Ramieri et al., 1990, 1992b;
Hilliges et al., 1995; Johansson et al., 1999). This marker
is effective for identifying and quantifying unmyelinated
intraepidermal nerves, a class that is frequently affected
in sensory and sensory-motor neuropathies (Barohn,
1998; McArthur et al., 1998; Verzé et al., 2000).
It has been suggested that GAP-43 immunoreactivity is
a sign of neuronal plasticity (Benowitz and Routtemberg,
1997; Oestreicher et al., 1997). In this report we compared
GAP-43 to PGP 9.5 to determine where remodeling in the
periphery nervous system normally takes place.
Our immunocytochemical findings of GAP-43-ir nerve
structures in the hand are in agreement with the known
anatomical distribution as derived from clinical neuroanatomical (silver and gold staining) and electrophysiological
studies. We observed the presence of GAP-43 immunoreactivity in a large population of nerve fibers in this highly
innervated region of the human skin. GAP-43-ir fibers
were particularly present in the epidermis, excluding the
stratum corneum, and the subepidermal layer, where
their density was comparable to that of PGP9.5-ir structures. This observation confirms the data of our previous
study on the rat lower lip, in which we similarly demonstrated the presence of a large number of GAP-43-ir fibers
in the epithelium of both skin and mucosa (Verzé et al.,
1999). In humans, GAP-43-ir fibers (Fantini and Johansson, 1992; Del Fiacco et al., 1994; Verzé et al., 2000) and
GAP-43 mRNA (Schmidt et al., 1991) have been described
in the sensory and autonomic nervous system. The detection of PGP 9.5-positive Merkel cells, as well as nerve
fibers related to Merkel cells in the human epidermis, is in
agreement with previous findings in different regions of
human skin and oral mucosa (Ramieri et al., 1992a, b).
There were notable differences between the GAP-43 and
the PGP 9.5 immunostaining. We detected GAP-43 immunoreactivity only in proximity to a few Merkel cells and
Meissner corpuscles. We suggest that the different expressions of these two neuronal markers indicate different
degrees of function in the Merkel cells (Misery and Gaudillere, 1996; Verzé et al., 1999) and Meissner corpuscles.
Meissner corpuscles in particular are widely regarded as
multiafferent receptor organs that may have nociceptive
capabilities, in addition to being low-threshold mechanoreceptors (Pare et al., 2001, 2002).
In the dermis, all nerve fibers were found to label with
PGP 9.5, whereas a more restricted pattern was observed
for GAP-43. The deeper nerve trunks and fibers were less
intensely stained for GAP-43 than for PGP 9.5. A basal
expression of GAP-43 in autonomic structures innervating
the sweat glands and vessels is in agreement with previous findings in human (Fantini and Johansson, 1992) and
rat (Verzé et al., 1999) skin. Complex nervous structures
associated with hair follicles showed a wide distribution of
GAP-43 immunoreactivity comparable with that of PGP
9.5. The innervation of these nerve structures was previously documented in mice, in which hair-cycle-dependent
plasticity was shown to be present in skin and hair follicle
innervation. In particular, GAP-43 immunoreactivity ap-
472
VERZÉ ET AL.
peared to be related with the early anagen phase of the
hair cycle (Botchkarev et al., 1997).
It seems, therefore, that epidermal nerve endings
should be more involved in remodeling and plasticity than
the populations of fibers located in deeper regions, such as
the dermis. The high level of basal GAP-43 immunoexpression in the epidermis may be related to continuous
migration of the basal cells of the epidermis toward more
superficial layers; this migration, which results in a loss of
the target for a subpopulation of sensory nerve fibers,
could be one of the local stimuli promoting GAP-43 immunoexpression in the most superficial nerve fibers of the
skin (Fantini and Johansson, 1992; Verzé et al., 1999).
Similar conditions may be involved in the basal expression
of GAP-43 in the nerve structures of hairs in adult hairy
hand skin, in the absence of any abnormal condition.
The molecular nature of the signals that determine the
basal expression of GAP-43 is unknown, but the high
density of GAP-43-ir nerve fibers in the basal layer of the
epidermis suggests the existence of tight contacts, as well
as a possible interaction between keratinocytes and nerve
structures (Hsieh et al., 1996). Intense nerve growth factor (NGF)-like immunoreactivity has been observed in rat
keratinocytes, excluding the stratum corneum (English et
al., 1994). In a recent report we demonstrated an almost
complete loss of epidermal innervation in a human sensory neuropathy induced by genetically-derived alteration
of NGF receptor expression (Verzé et al., 2000). It is possible that NGF is a signaling molecule that induces nerve
plasticity in the epidermis and therefore determines the
expression of GAP-43. In support of this hypothesis, in
vitro studies have shown that NGF increases GAP-43
expression in PC12 cells, as well as in neurons of the
superior cervical ganglia (Federoff et al., 1988).
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