1 Laboratory for Cell Culture Development, RIKEN Brain Science Institute,
Saitama 351-0198, Japan
2 Molecular Neuropathology Group, RIKEN Brain Science Institute, Saitama
351-0198, Japan
3 Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama
351-0198, Japan
4 Division of Gene Function in Animals, Nara Institute of Science and
Technology, Nara 630-0192, Japan
5 Immune System Development Group, RIKEN Research Center for Allergy and
Immunology, Kanagawa 230-0045, Japan
6 Laboratory of Reproductive and Developmental Toxicology, National Institute of
Environmental Health Sciences, Research Triangle Park, NC 27709, USA
* Author for correspondence (e-mail: masahisa{at}brain.riken.go.jp)
Accepted 7 January 2004
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SUMMARY |
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Key words: Bone morphogenetic protein, Type I receptor, Hair follicle cycling, Mouse
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Introduction |
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Tumor necrosis factor receptor; super-family molecules, such as
ectodysplasin receptor (EDAR), X-linked ectodysplasin-A2 receptor (XEDAR) and
TROY, and their ligand, ectodysplasin (EDA); and other related signal
transduction molecules reportedly initiate guard hair follicle and some skin
appendage development (Laurikkala et al.,
2002; Srivastava et al.,
2001
; Kojima e al.,
2000
). Wnt signals and ß-catenin were suggested to play
important signaling roles in later stages of HF development
(Gat et al., 1998
;
Huelsken et al., 2001
;
Kishimoto et al., 2000
).
Bone morphogenetic protein (BMP) signaling has been found to contribute to
various developmental processes, including rapid proliferation and
morphogenetic movements during the gastrulation period (reviewed by
Mishina, 2003;
Furuta et al., 1997
). During
HF development, BMPs are expressed in the hair placode and surrounding
mesenchyme, and may participate in stimulating HF induction. For example, BMP
family members such as BMP2, BMP3, BMP4 and BMP7 are expressed in the skin and
HFs from the embryonic stage to adult
(Lyons et al., 1989
;
Takahashi and Ikeda, 1996
;
Stelnicki et al., 1998
;
Wilson et. al., 1999
;
Botchkarev et al., 2001
). The
BMP-neutralizing protein Noggin, which interacts with BMP4, triggers HF
induction in the hair placode, suggesting that BMP downregulation may be a cue
to start HF development (Botchkarev et al.,
1999
; Botchkarev et al.,
2002
) (reviewed by Botchkarev,
2003
). In hair placode development, BMPs and sonic hedgehog (SHH)
expressions are genetically located downstream of ß-catenin signaling
(Noramly et al., 1999
;
Huelsken et al., 2001
). SHH
also regulates HF growth and morphogenesis
(Oro and Higgins, 2003
;
Callahan and Oro, 2001
;
Chuong et al., 2000
;
Dlugosz, 1999
). ß-Catenin
is necessary in determining the fate of stem cells that form follicular
keratinocytes, whereas this is not the case for an epidermal fate decision
(Jamora et al., 2003
).
At the initiation of the anagen phase, follicle progenitor cells of the
epidermis induce mesenchymal condensation to form dermal papilla, and then
generate proliferating matrix cells. Those epidermal cells further
differentiate into hair shaft cells. Additionally, some of these stem cells
also form the basal layer of the epidermis. Recent evidence suggests that the
initiation of feather placodes in chickens is controlled by positive and
negative signals mediated by FGFs and BMPs, respectively
(Song et al., 1996;
Jung et al., 1998
). BMPs
signaling is exerted through a complex of type I (BMPRI) and type II receptors
(BMPRII). BMPR1A (alternatively known as ALK3) is one of three type I
receptors for BMPs. Unfortunately, disrupting Bmpr1a in mice blocked
mesoderm formation and resulted in intrauterine death before embryonic day 7.5
(E7.5) (Mishina et al., 1995
),
preventing further investigation into the function of BMP signaling in HF
development through BMPR1A, the receptor with the highest affinity for
BMP4.
In this study, we examined the role of BMP signaling through BMPR1A during generation and maturation of HFs using mutant mice with Bmpr1a deleted in HFs in skin. We found abnormal HF differentiation and reduced cell growth of interfollicular epidermal cells in the fetal skin of these hair-specific Bmpr1a knockout mice (Hair-Bmpr1a KO mice). In postnatal Hair-Bmpr1a KO mice, a reduction in the number of HFs was apparent in 2-week-old and 10-month-old mutant mice which were hairless in affected regions. Epithelial cells in the hair matrix were located separately covering the luminal surface of open hair canals; and, in the hair shaft, inner root sheath (IRS) development was severely impaired. Furthermore, HF epithelial cells of the older mutant mice also had hardly incorporated BrdU. Taken together, our results strongly suggest that BMPR1A signaling is not only essential for the differentiation of the HF in the developmental stage, but also important for epidermal cell proliferation or differentiation in hair cycle renewal during adult life.
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Materials and methods |
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Immunohistochemistry
Frozen cryosections (15 µm) were treated with 3%
H2O2, incubated with blocking buffer (PBS containing
0.01% Triton X and 1.5% normal goat serum), and incubated overnight at 4°C
with monoclonal mouse anti-bromodeoxyuridine (1:100, DAKO),
anti-phospho-histone H3 (rabbit polyclonal, 1:300, Upstate), anti Met (goat
polyclonal antibody, SANTA CRUZ) and PDGFR- (rat monoclonal antibody,
Pharmingen). Sections were incubated in biotinylated anti-mouse IgG (1:300,
Vector Laboratories), horseradish peroxidase conjugated anti-rabbit IgG (MBL)
and horseradish peroxidase conjugated anti-rat IgG (Jackson Immunoresearch)
antibody diluted in blocking buffer, and DAB reaction. Primary antibodies used
were monoclonal anti ß-Catenin (1:500, Sigma, 15B8), polyclonal
anti-keratin 5 (1:1000, Covance), polyclonal anti-keratin 6 (K6; kindly
provided by Dr Shimomura) (Aoki et al.,
2001
), anti-TRAF6 (goat polyclonal antibody, Santa Cruz),
anti-notch (goat polyclonal antibody, Santa Cruz) and anti-EGFR (goat
polyclonal antibody, Santa Cruz). FITC-conjugated goat anti-mouse IgG (1:200,
Jackson Immunoresearch), Cy3-conjugated goat anti-rabbit IgG (1:800, Jackson
Immunoresearch) and Cy3-conjugated anti-goat IgG (Chemicon) second antibodies
were used. Sections were counterstained with Hoechst (Calbiochem).
Analysis of apoptosis
Apoptotic cells were detected by TUNEL assay on 4% paraformaldehyde fixed
cryosections of E15-16 limbs by using the ApopTag Peroxidase kit
(Intergen).
In situ hybridization
In situ hybridization using digoxigenin-labeled (Roche) cRNA probes was
performed on cryosections. Riboprobes for Bmpr1a and Shh
were generated as described previously
(Mishina et al., 1995;
Kato et al., 2001
). Skin
sections were fixed in 4% formaldehyde, acetylated with 0.5% acetic anhydride
in 0.1 M triethanolamine (pH 8.0) for 10 minutes, and rinsed in PBS. The
slides were prehybridized in hybridization buffer without cRNA probe at room
temperature for 2 hours and hybridized using a hybridization buffer (50%
formamide, 5xSSPE, 1 mg/ml yeast tRNA, 0.2% SDS) containing 1 µg/ml
cRNA probe at 60°C overnight. Slides were washed in 2xSSC containing
50% formamide at 60°C for 1 hour. Hybridization was detected using an
anti-DIG Fab (Roche) coupled to alkaline phosphatase using NBT/BCIP.
X-gal histochemistry staining
Frozen sections (15 µm) were fixed in 4% paraformaldehyde (pH 7.5) for
20 minutes, then washed and incubated with PBS containing 0.01% sodium
deoxycholate, 0.02% NP40 and 1 mM MgCl2 (lacZ wash buffer)
for 3 hours. For combined X-gal staining with Hematoxylin-Eosin, overnight
X-gal staining was processed with PBS containing 1 mg/ml X-gal
(5-bromo-4-chloro-3-indoyl-ßD-galactopyranoside), 5 mM K-ferrocyanide, 5
mM K-ferricyanide, 0.01% sodium deoxycholate, 0.02% NP40, 1 mM
MgCl2 at 37°C protected from light, then Hematoxylin-Eosin
staining was processed.
BrdU-labeling experiments
BrdU (3 mg/100 g body weight, cell proliferation KIT, Amersham Bioscience)
was injected to mice subcutaneously, and skin samples were taken 3 hours after
injection, fixed in 4% paraformaldehyde and processed for
immunohistochemistry.
Electron-micrograph
For electronmicroscopic observation of the skin, a postnatal day 30
Hair-Bmpr1a KO mouse and a control mouse
(Emx1Cre/+Bmpr1aflox/) were fixed 2.5%
glutaraldehyde and 4% paraformaldehyde. After fixation, the tissue samples
were postfixed with 1% (w/v) osmium tetroxide in 0.1 M PB, dehydrated in a
graded ethanol series and embedded in epoxy resin (EPON812 and Araldyte CY212,
TAAB, Aldermaston, UK). For electron microscopic observation, the skin was
sectioned into 80 nm slices with an ultramicrotome (Ultracut-R, Leica,
Heidelberg, Germany). Ultrathin sections were stained with uranyl acetate and
lead citrate. Electron micrographs recorded on imaging plates through an LEO
912 electron microscope (LEO electron microscopy, Oberkochen, Germany) were
scanned and digitized by an FDL 5000 imaging system (Fuji Photofilm, Tokyo,
Japan).
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Results |
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Discussion |
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An abnormal pattern of HF structure was observed in Hair-Bmpr1a KO
mice in both the first and second anagen phases of hair cycle development.
Still, part of the HF induction normally occurred in Hair-Bmpr1a KO
mice during the first anagen. Because, the induction of HF starts at about E14
in the limbs, where Emx1-Cre is expressed as early as E13.5, it is
likely that BMPR1A signaling is not required to initiate hair follicle
genesis. EDA, EDAR and TRAF6 could be the important triggers for this
induction (Laurikkala et al.,
2002; Srivastava et al.,
2001
; Kojima et al.,
2000
). Relatively normal expression levels of these genes found in
Hair-Bmpr1a KO mice support this idea. However, we cannot completely
exclude the possibility that some of the cells in HFs may retain enough BMPR1A
to induce normal HF development.
How does BMPR1A signaling contribute to HF development? Kulessa et al. have
previously reported that disrupting the BMP signal in HF-specific mice
overexpressing Noggin selectively inhibited the formation of the
medulla and the hair shaft. However, Hair-Bmpr1a KO mice showed
impaired IRS formation, as indicated by a lack of keratin6 expression, and
despite the fact that notch expression, an early marker of IRS
(Kopan and Weintraub, 1993),
was relatively normal. Thus, although IRS progenitor cells in
Hair-Bmpr1a KO mice are likely to be generated, further
differentiation involving IRS-keratin 6 expression in the absence of BMPR1A
signaling was impaired. These results suggest that BMP signaling, which is
essential for early differentiation of IRS, may not be transduced by BMPR1A,
and that overexpressed Noggin interferes with the other receptors
mediating signaling in the early stage of IRS differentiation.
We found malformation of HFs, impaired cell cycling of matrix cells, and complete hair loss in the second anagen. Impaired HF development can be seen in P14 Hair-Bmpr1a KO mice because HF formation in these mice was already impaired in the first anagen. We found notch expression in abnormal HF in Hair-Bmpr1a KO mice, which suggests that the commitment to the IRS cell lineage occurs normally. Although, IRS-keratin 6, a late differentiation marker for both Huxley's and Henle's layers, was present in the hair follicle bulb of Hair-Bmpr1a KO mice (Fig. 5E), the structures were missing (Fig. 5J). These differentiation impairments strongly suggest that BMPR1A signaling plays an essential role in the differentiation of IRS. Abnormal HFs in our mice have only multiple layers of ORS and an immature hair shaft that produce cysts composed of keratinized debris. Therefore, our results suggest that the abnormal differentiation of IRS leads to abnormal HF formation that may eventually impair the cell cycling of epithelial cells.
From these finding, we suspect that bulge formation, originating from HF
stem cells, is also affected in the absence of BMPR1A signaling. But, how does
the absence of Bmpr1a contribute to the formation of the bulge
structure? The skin of Hair-Bmpr1a KO mice appears to have normal
skin cycling with no abnormalities observed in the basal layer of skin except
hair loss (Fig. 7H,J). However,
bulge structure is therefore likely to unformed in adequate region, which
interfere with receiving the key regulator regeneration signals.
Interestingly, the expression area of TRAF6, which is genetically down stream
of XEDAR or TROY (Laurikkala et al.,
2002; Srivastava et al.,
2001
; Kojima et al.,
2000
), was increased in the HFs of the Hair-Bmpr1a KO
mice compared with control (Fig.
6). The constitutive expression of TRAF6 may represent the
inhibition of TRAF6 signaling in the Hair-Bmpr1a KO mice, if feedback
regulation is the case. TRAF6 mutant mice are hypohidrotic (anhidrotic), with
ectodermal dysplasia (HED) (Naito et al.,
2002
). Moreover, impaired TRAF6 signaling may contribute to the
pathogenesis of a certain type of abnormality in the formation of HF and
sebaceous gland that has impaired formation of bulge architecture. Further
investigations of Hair-Bmpr1a KO mice and TRAF6 mutant mice might
reveal a connection between these two signaling pathways. The development of a
perinatal stage-specific disruption system for Bmpr1a in a
HF-specific manner would facilitate this comparison.
A similar phenotype, in which the inner root sheath is impaired in a
similar fashion as, in Hair-Bmpr1a KO mice, was recently observed in
mice harboring a mutation of the ß-catenin gene
(Huelsken et al., 2001),
suggesting that ß-catenin is necessary for the determination of the cell
fate of stem cells to form follicular keratinocytes. Notably, abnormal hair
shaft differentiations, subsequent loss of hair, and cyst formation in widened
canals in the ß-catenin mutant mice are the same phenotypes as seen in
our mice. Interestingly, the expression of cytekeratin 17, as a marker of the
ORS, is upregulated in mutant mice. Based upon the results of ß-catenin
KO mice, which show the loss of BMP and Shh expression in the mice, the
expression of BMP and Shh is controlled by ß-catenin in a complex process
determining the fate of skin stem cells (reviewed by
Oro and Scott, 1998
;
Barsh, 1999
;
Huelsken et al., 2001
). In
Hair-Bmpr1a KO mice, the expression areas of ß-catenin and Shh
were increased. These results suggest that BMPR1A signaling and ß-catenin
signaling may be responsible for different functions in HF development and
presumably interact with each other. These signals may be using a common
downstream pathway; however, it is also possible that they act in parallel to
regulate HF differentiation.
In situ hybridization demonstrated broad expression of Bmpr1a in
HFs. The reduction of IRS was obvious in Hair-Bmpr1a KO mice; yet,
the ORS formed multiple layers in the mice. In human studies, both BMPR1A and
BMPR1B were detected in the HFs in adult and fetal skin
(Hwang et al., 2001). Perhaps
BMP signaling, through BMPR1B, compensates for the loss of BMPR1A signaling
during the generation of the ORS. An unsolved problem of interest is how to
define the unique function of BMP signaling through each type I receptor in
the HF. Analyzing BMPR1B KO mice may address this question. Taken together,
this suggests that BMPR1A signaling has a role in differentiation during
maturation of the IRS from hair matrix epithelial cells. Abnormal hair cycling
occurs in the absence of BMPR1A signaling, regardless of the relatively normal
expression levels of other growth regulation genes for HFs, suggesting that
BMPR1A signaling is one of the key components for hair cycling.
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ACKNOWLEDGMENTS |
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Footnotes |
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Since the submission of this paper, one paper has appeared demonstrating
that importance of BMP signaling for development of IRS in the mouse
(Kobielak et al., 2003).
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