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Establishment of cadherin-based intercellular junctions in the dermal papilla of the developing hair follicle.

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Establishment of Cadherin-Based
Intercellular Junctions in the Dermal
Papilla of the Developing
Hair Follicle
Department of Biology, Graduate School of Science, Osaka University, Toyonaka,
Osaka, Japan
During hair follicle development, mesenchymal cells aggregate to form
the dermal papilla with hair-inducing activity. However, the cellular mechanisms underlying the aggregative behavior of dermal papilla cells are less
known. The present study demonstrates that cadherin-based intercellular
junctions interconnect dermal papilla cells in developing hair follicles of
mice. It is shown that as mesenchymal cells aggregate to be surrounded by
epithelium in developing hair follicles, cadherin-11 comes to exhibit the
dotted patterns of distribution. The appearance of the dot-like distribution
of the molecule is concomitant with the formation of intercellular junctions
in the mesenchymal aggregate, which make a tightly packed population of
cells with little extracellular space. At later stages of the development,
although extracellular space reappears in the dermal papilla, the cells
remain interconnected by well-developed intercellular junctions, where cadherin-11 as well as ␤-catenin is localized. Taking into consideration the
normal hair development in cadherin-11 mutant mice, it might be that
multiple cadherins are responsible for the establishment of intercellular
junctions in the dermal papilla and serve to maintain the aggregative
behavior of the cells. Anat Rec Part A 270A:97–102, 2003.
2003 Wiley-Liss, Inc.
Key words: cadherin-11; intercellular junction; cell rearrangement; dermal papilla; hair follicle
At the onset of hair follicle development a subpopulation
of dermal mesenchymal cells starts to gather just below
the epidermal placode. The mesenchymal aggregate is
subsequently surrounded by the elongating follicular epithelium to become the dermal papilla with hair-inducing
activity (Oliver, 1967, 1970; Ibrahim and Wright, 1977;
Jahoda et al., 1984; Horne et al., 1986; Hardy, 1992;
Reynolds and Jahoda, 1992; Kamimura et al., 1997). It
has been suggested that aggregative behavior is the essential feature of dermal papilla cells associated with the
hair-inducing activity. For instance, cultured dermal papilla cells of early passage numbers retain their aggregative and hair-inducing activities, whereas those of later
passage numbers lose these activities (Jahoda and Oliver,
1984; Horne et al., 1986; Kishimoto et al., 1999). When
dermal papilla cells are cultivated in medium conditioned
by keratinocytes, both of the activities can be maintained
even after dozens of passages (Inamatsu et al., 1998).
It was previously reported that definite junctions with
electron-dense materials were present between dermal
papilla cells but not between other dermal fibroblasts
Grant sponsor: Japan Science Society.
Daisuke Nanba’s present address is Department of Medical
Biochemistry, School of Medicine, Ehime University, Shitsukawa, Shigenobu-cho, Ehime 791-0025, Japan.
*Correspondence to: Yohki Hieda, Ph.D., Department of Biology, Graduate School of Science, Osaka University, 1-16 Machikaneyama, Toyonaka, Osaka 560-0043, Japan. Fax: ⫹81-6-68505817. E-mail:
Received 21 June 2002; Accepted 21 September 2002
DOI 10.1002/ar.a.10012
(Hashimoto, 1970), suggesting that formation of intercellular junctions may contribute to the aggregation of dermal mesenchymal cells, resulting in the dermal papilla
formation. A variety of cell adhesion-related molecules
have so far been shown to be expressed in mesenchymal
aggregates of developing hair follicles, including the neural cell adhesion molecule (NCAM), the ␣1, ␣5, ␣9, and ␤1
subunits of integrins (Kaplan and Holbrook, 1994; Wang
et al., 1995; Hardy and Vielkind, 1996; Almond-Roesler et
al., 1997; Müller-Röver et al., 1998), and the chondroitin
sulfate proteoglycan of versican (Kishimoto et al., 1999;
Harris and Jahoda, 2001). No cell adhesion molecule, however, has been associated with the intercellular junctions,
leaving the molecular nature of the junctions to be clarified. In addition, detailed ultrastructural information has
not been available on how intercellular junctions are established between mesenchymal cells during the dermal
papilla formation.
Ultrastructurally recognizable intercellular junctions
such as adherens junctions and desmosomes in epithelial
cells and synapses in neurons are mediated primarily by
the cadherin family of cell adhesion molecules, which play
crucial roles in tissue morphogenesis and in signaling
events (Green and Gaudry, 2000; Takeichi et al., 2000;
Yagi and Takeichi, 2000; Nagafuchi, 2001). Although little
information is available on the expression profile of cadherins in mesenchymal cells of developing hair follicles,
cells of the dermal papilla and dermal sheath have been
shown to express mRNA for cadherin-11 (Simonneau et
al., 1995). In the present study, we show that intercellular
junctions containing cadherin-11 are established in the
dermal papilla of the developing hair follicle and that
formation of the dermal papilla involves dynamic rearrangements of cells. Cadherin-11 is the only member of
the family whose expression has been reported in the
dermal papilla. Since cadherin-11 (–/–) mice, however,
exhibit normal hair development (Horikawa et al., 1999;
Manabe et al., 2000), multiple cadherins are likely involved in the establishment of intercellular junctions during the dermal papilla formation.
Mouse Embryos and Organs
Embryos were obtained from ddY strain mice (Nihon
SLC, Hamamatsu, Japan). The discovery of the vaginal
plug was designated as embryonic day 0 (E0). The back
skin was dissected from embryos at E15 and E17, and
from newborn mice at postnatal day 1 (P1).
The following primary antibodies were used: mouse
monoclonal antibodies specific for E-cadherin and ␤-catenin (Transduction Laboratories, Lexington, KY), rabbit
polyclonal antibody against cadherin-11 (Zymed Laboratories, San Francisco, CA), and rabbit polyclonal antibody
to type I collagen (gift from Drs. Yoneda and Kimata, Aichi
Medical University, Japan). Secondary antibodies used
were rhodamine-conjugated goat anti-mouse immunoglobulin G (IgG) (Chemicon, Temewla, CA), fluorescein isothiocyanate (FITC)-conjugated goat anti-rabbit IgG (Cappel, Durham, NC), and 10 nm of colloidal gold-conjugated
goat anti-mouse IgG and goat anti-rabbit IgG (British
Biocell International, Cardiff, UK).
Immunofluorescence Microscopy
Freshly prepared skin fragments were embedded in
OCT compound and frozen in liquid nitrogen. Tissue sections of 6-␮m thickness were fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) at 4°C for 10 min
or in methanol at –20°C for 10 min. The specimens were
treated with 0.5% Triton X-100 in PBS for 10 min and
subsequently with 1% bovine serum albumin (BSA). Then
they were incubated with primary antibodies for 1 hr,
washed in PBS, and incubated with secondary antibodies
for 1 hr. After a wash in PBS, the sections were mounted
with PBS containing 50% glycerol and 0.1% p-phenylenediamine and examined under an Olympus AX-70 or BX-50
epifluorescence microscope.
Electron Microscopy
For conventional electron microscopy, freshly prepared
skin fragments were fixed in 0.1 M cacodylate buffer (pH
7.3) containing 2.5% glutaraldehyde and 2% paraformaldehyde and were then immersed in 1% osmium tetraoxide
in the same buffer. Dehydration in a gradient series of
ethanol and propylene oxide was followed by embedding in
PolyBed 812 (Polysciences, Warrington, PA). Ultrathin
sections were cut on a Reichert ultramicrotome (Leica,
Wien, Austria), stained with uranyl acetate for 2 min and
with lead citrate for 3 min, and observed with a JEOL
1200EX electron microscope.
For immunoelectron microscopy, skin fragments were
fixed in 4% paraformaldehyde in 0.1 M phosphate buffer
(pH 7.3) at 4°C overnight. Dehydration in a gradient series of ethanol on ice was followed by embedding in LR
white resin (London Resin, Hampshire, UK). Ultrathin
sections were cut on an ultramicrotome and mounted on
70-mesh nickel grids supported by Formvar films. Incubation in all cases was conducted by floating grids section
side down on drops of reaction or washing media. The
sections were treated with 1% BSA in PBS for 30 min.
They were then incubated with primary antibodies at 4°C
overnight, washed in PBS containing 0.1% Triton X-100,
and incubated with 10 nm of colloidal gold-conjugated
secondary antibodies for 2 hr. Washes in PBS containing
0.1% Triton X-100 were followed by staining with uranyl
acetate for 3 min and with lead citrate for 30 sec.
We examined the distribution patterns of cadherin-11
and the ultrastructural process of the dermal papilla formation in developing mouse pelage hair follicles at E15,
E17, and P1. Immunofluorescence microscopy showed
that expression of the cadherin-11 molecule was restricted
to the mesenchyme adjacent to epithelium (Fig. 1), being
consistent with the expression pattern of the transcripts
(Simonneau et al., 1995). Close inspection revealed
changes in the distribution pattern of cadherin-11 in mesenchymal cells during formation of the dermal papilla. In
the initial mesenchymal aggregate of the E15 developing
follicle, cadherin-11 was distributed uniformly along the
cell surfaces (Fig. 1A, D). Electron microscopy of the mesenchymal aggregate revealed that junction-like structures
had not formed between cells, though the cells had extended numerous protrusions to make contact with their
neighbors (Fig. 2A). Collagen fibers were present in the
extracellular space, which was confirmed by positive
staining for type I collagen in the mesenchymal aggregate,
Fig. 1. Distribution of cadherin-11 in developing hair follicles. Cadherin-11 expression is restricted to mesenchyme at all the stages examined. At E15, cadherin-11 shows relatively uniform distribution along
cell surfaces in the mesenchymal aggregate (A, arrow; D, for closer
inspection). The dotted distribution of cadherin-11 is noted in the dermal
papilla at E17 (B, arrow; E, for closer inspection) and becomes more
evident at P1 (C, arrow; F, for closer inspection). Mesenchymal cells
surrounding the follicular epithelium at E17 and P1 are also stained in a
dot-like pattern (arrowheads). No signal was detected when the primary
antibodies were omitted (data not shown). Arrows indicate the mesenchymal aggregate and dermal papilla. Scale bars ⫽ 25 ␮m (A–C); 5 ␮m
though the staining intensity was weaker than that in
other dermal mesenchymes (Fig. 3A).
In the developing hair follicles at E17, cadherin-11
tended to exhibit the dot-like patterns of distribution in
the presumptive dermal papilla, which had just become
surrounded by the epithelium, and in the dermal sheath
(Fig. 1B, E). Noticeably, concomitant with the appearance
of the dot-like distribution of the molecule, small but ultrastructurally recognizable intercellular junctions were
found between the cells (Fig. 2B). The dermal papilla cells
were tightly packed or stuck along their entire surfaces,
with little extracellular space. Staining for type I collagen
was hardly detected (Fig. 3B).
The dot-like distribution of cadherin-11 became more
evident in the dermal papilla of P1 hair follicles (Fig. 1C,
F). Ultrastructurally, although the extracellular space
had widened again, dermal papilla cells kept their adherence to each other at the tips of their extensions, where
definite intercellular junctions with electron-dense materials had become established (Fig. 2C). The extracellular
space of the dermal papilla was abundant in amorphous
materials rather than in collagen fibrils. Only limited
staining was observed for type I collagen (Fig. 3C). Immunoelectron microscopy revealed cadherin-11 as well as
␤-catenin to be indeed localized at the intercellular junctions in the dermal papilla (Fig. 4).
The present study aimed to clarify the morphological
and molecular bases underlying the aggregation of mesenchymal cells during dermal papilla formation. It was
reported earlier that junction-like structures were present
between dermal papilla cells but not between other dermal fibroblasts (Hashimoto, 1970) and that cadherin-11
mRNA was expressed in the dermal papilla (Simonneau et
al., 1995). We showed here that cadherin-11 expressed in
mesenchymal aggregates became distributed in dot-like
patterns during dermal papilla formation, which was coincident with the appearance of junctional structures between the cells. As revealed by immunoelectron microscopy, cadherin-11 as well as ␤-catenin was localized at the
intercellular junctions established in the dermal papilla.
These findings demonstrate that dermal papilla cells in
developing hair follicles become interconnected by cadherin-based intercellular junctions.
Although mesenchymal cells of the initial aggregate,
before it was surrounded by epithelium, made contact
with their neighbors by extending protrusions, junctionlike structures were not detected at cell contact sites, and
cadherin-11 was distributed uniformly along cell surfaces.
Ultrastructurally recognizable intercellular junctions first
appeared at the subsequent stage when the dermal papilla
Fig. 2. Electron micrographs of aggregating mesenchymal
cells in the developing hair follicles. A: Cells of the mesenchymal
aggregate at E15 have extended numerous protrusions to make
contact with their neighbors; however, almost no junction-like
structure has formed between cells. In the extracellular space,
collagen fibrils are present (arrowheads). B: The dermal papilla at
E17 makes a tightly packed population of cells. Note that junctionlike structures have formed between the cells (arrows). C: The
extracellular space has been restored in the dermal papilla at P1,
where amorphous materials rather than collagen fibrils are abundant. Note, however, that the cells remain connected by the developed intercellular junctions (arrows). Insets, higher magnification of boxed regions. Scale bars ⫽ 1 ␮m; 200 nm in insets.
made a tightly packed population of cells with little extracellular space. Together with the concomitant redistribution of cadherin-11 to dot-like patterns at cell boundaries,
cadherin-mediated adhesion appears to become activated
or promoted in the cells. It is not clear at present whether
the formation of cadherin-based intercellular junctions is
responsible for the “compaction” of the cells. Alternatively,
it would also be possible that degradation of the extracellular matrix, as revealed by electron microscopy and immunostaining for interstitial collagens, results in close
apposition of cell surfaces, allowing the cells to develop the
intercellular junctions. The compaction of dermal papilla
cells was followed by restoration of extracellular space in
the dermal papilla, where amorphous materials rather
than collagen fibrils were abundant. Cells of the dermal
papilla remained connected, however, by well-developed
intercellular junctions containing cadherin-11 and ␤-catenin, suggesting that establishment of cadherin-based intercellular junctions serves to keep the cells from separating from one another.
It has been well documented that the aggregative behavior of dermal papilla cells is closely coupled to their
hair-inducing activity (Jahoda and Oliver, 1984; Horne et
al., 1986; Inamatsu et al., 1998; Kishimoto et al., 1999).
The aggregative and hair-inducing activities of cultured
dermal papilla cells can be maintained by conditioned
medium from keratinocyte cultures and by Wnt ligands
(Inamatsu et al., 1998; Kishimoto et al., 1999, 2000) and
that the Wnt signaling components such as frizzled and
␤-catenin are expressed in dermal papilla cells (Kishimoto
et al., 2000). In addition, Wnt signaling was shown to
regulate cadherin-mediated cell adhesion (Bradley et al.,
Fig. 3. Distribution of type I collagen in developing hair follicles.
Tissue sections were double-stained for type I collagen (green) and
E-cadherin (red). The mesenchymal aggregate at E15 is positive for type
I collagen (A, arrow). However, note that the staining intensity in the
Fig. 4. Localization of cadherin-11 and ␤-catenin at intercellular junctions in the dermal papilla. Immunoelectron microscopy was performed
by using 10 nm of colloidal gold-conjugated secondary antibodies to
visualize the localization of cadherin-11 (A) and ␤-catenin (B) in the
developing hair follicle at P1. Specific labeling is observed for both
molecules at intercellular junctions in the dermal papilla. Scale bar ⫽ 100
1993; Hinck et al., 1994). Taken these and our present
findings together, it might be suggested that regulation of
cadherin-mediated adhesion of dermal papilla cells by
Wnt signaling is involved in the acquisition of their hairinductive activity.
Cadherin-11 is the only member of the family whose
expression has been reported in the dermal papilla (Simonneau et al., 1995) and confers adhesive activity on cells
(Okazaki et al., 1994; Kimura et al., 1995; Shibata et al.,
1996; Horikawa et al., 1999; Pishvaian et al., 1999; Shimoyama et al., 2000). Mice deficient in cadherin-11 were
recently shown, however, to exhibit normal hair development, surviving to the adult stage (Horikawa et al., 1999;
Manabe et al., 2000). This finding may suggest that multiple cadherins are expressed in the dermal papilla to be
involved in hair follicle development. Although cadherin-11 was reported to cooperate with N-cadherin in
somitogenesis (Horikawa et al., 1999) and to exhibit not
only homophilic binding but also heterophilic binding with
cadherin-8 (Shimoyama et al., 2000), neither N-cadherin
nor cadherin-8 is detectable in the dermal papilla (Nanba
aggregate is weaker than that in other dermal mesenchymes. At E17 (B)
and P1 (C), the collagen staining is hardly detectable or very limited in
the dermal papilla (arrows). Scale bar ⫽ 10 ␮m.
and Hieda, unpublished data). Identification of the repertoire of cadherins expressed in the dermal papilla should
provide a clue to elucidating the mechanism by which the
aggregative and hair-inducing activities are coupled.
The establishment of cadherin-based intercellular junctions in dermal papilla cells with aggregative behavior
suggests that their intercellular adhesivity is indeed increased. On the other hand, as we previously showed,
epithelial cells of the hair matrix-containing region, which
overlie to surround the dermal papilla, lose intercellular
junctions and show the decreased expression of desmosomal molecules, including the cadherin members desmogleins and desmocollins (Nanba et al., 2000). In contrast to
dermal papilla cells, these epithelial cells of the developing hair follicle likely have decreased intercellular adhesivity. As demonstrated in our recent study, the epithelial
adhesion system is also downregulated in the mammary
bud, where the mammary epithelial cells have very decreased intercellular adhesivity in comparison with the
overlying epidermal cells, which have a well-developed
adhesion system (Nanba et al., 2001). These observations
together support our proposal that the morphology of the
distal portion of the hair follicle, where the epithelium
surrounds the dermal papilla, results from engulfment of
dermal papilla cells with increased intercellular adhesivity by the overlying epithelial cells with decreased adhesivity (Nanba et al., 2000).
This work was supported in part by a Sasakawa Scientific Research Grant from the Japan Science Society to
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