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First published online January 13, 2009
doi: 10.1242/10.1242/dev.021295
Research Report |
1 Center for Animal Resources and Development (CARD), Kumamoto University,
Kumamoto 860-0811, Japan.
2 Global COE `Cell Fate Regulation Research and Education Unit', Kumamoto
University, Kumamoto 860-0811, Japan.
3 Department of Geriatric and Environmental Dermatology, Nagoya City University
Graduate School of Medical Sciences, Nagoya 467-8601, Japan.
4 Department of Dermatology, Hokkaido University Graduate School of Medicine,
Sapporo 060-8638, Japan.
5 Department of Pharmacology, Graduate School of Medicine, Kyoto University,
Kyoto 606-8501, Japan.
6 Department of Molecular Biochemistry, Hokkaido University, Sapporo, Hokkaido
060-8638, Japan.
7 Cancer and Developmental Biology Laboratory, National Cancer
Institute-Frederick, NIH Frederick, MD 21702, USA.
8 Department of Cancer Biology, Max-Delbrück-Center for Molecular Medicine,
13125 Berlin, Germany.
9 Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo
113-0032, Japan.
* Author for correspondence (e-mail: gensan{at}gpo.kumamoto-u.ac.jp)
Accepted 17 November 2008
SUMMARY
β-catenin signaling is one of the key factors regulating the fate of hair follicles (HFs). To elucidate the regulatory mechanism of embryonic HF fate determination during epidermal development/differentiation, we analyzed conditional mutant mice with keratinocytes expressing constitutively active β-catenin (K5-Cre Catnb(ex3)fl/+). The mutant mice developed scaly skin with a thickened epidermis and showed impaired epidermal stratification. The hair shaft keratins were broadly expressed in the epidermis but there was no expression of the terminal differentiation markers K1 and loricrin. Hair placode markers (Bmp2 and Shh) and follicular dermal condensate markers (noggin, patched 1 and Pdgfra) were expressed throughout the epidermis and the upper dermis, respectively. These results indicate that the embryonic epidermal keratinocytes have switched extensively to the HF fate. A series of genetic studies demonstrated that the epidermal switching to HF fate was suppressed by introducing the conditional mutation K5-Cre Catnb(ex3)fl/+Shhfl/- (with additional mutation of Shh signaling) or K5-Cre Catnb(ex3)fl/+BmprIAfl/fl (with additional mutation of Bmp signaling). These results demonstrate that Wnt/β-catenin signaling relayed through Shh and Bmp signals is the principal regulatory mechanism underlying the HF cell fate change. Assessment of Bmp2 promoter activities suggested a putative regulation by β-catenin signaling relayed by Shh signaling towards Bmp2. We also found that Shh protein expression was increased and expanded in the epidermis of K5-Cre Catnb(ex3)fl/+BmprIAfl/fl mice. These results indicate the presence of growth factor signal cross-talk involving β-catenin signaling, which regulates the HF fate.
Key words: Skin, Hair follicle (HF), Wnt, β-catenin, Bmp, Shh, Cell fate
INTRODUCTION
Recent studies have implicated members of the Wnt/β-catenin signaling
pathway as vital regulators of the epithelial-mesenchymal interactions that
specify the development of hair follicles (HFs)
(Fuchs, 2007
;
Yu et al., 2008). The
essential role of Wnt/β-catenin signaling during HF morphogenesis has
been suggested by transgenic and knockout mouse studies
(Andl et al., 2002;
Gat et al., 1998;
Huelsken et al., 2001;
Lo Celso et al., 2004). Recent
studies using embryos have revealed that embryonic HF fate change, HF
differentiation and its excessive induction are induced by stabilized
β-catenin (Narhi et al.,
2008; Zhang et al.,
2008).
Besides Wnt/β-catenin signaling, Bmp (bone morphogenetic protein) and
Shh (sonic hedgehog) signaling have also been suggested to regulate HF
formation. Bmp signaling has been suggested to regulate HF induction and the
patterning of follicles within the skin by repressing the placode fate
(Botchkarev et al., 1999;
Jamora et al., 2003;
Jiang et al., 1999;
Noramly and Morgan, 1998;
Rendl et al., 2008). Shh
signaling regulates HF cell proliferation and morphogenesis
(Chiang et al., 1999;
St-Jacques et al., 1998).
However, the mechanisms involved in the downstream effects of
Wnt/β-catenin signaling to regulate HF fate are poorly understood.
To elucidate whether the embryonic HF fate change is regulated by several
growth factor signaling pathways associated with Wnt/β-catenin signaling,
a conditional cutaneous-specific recombination strategy was employed using a
stabilized β-catenin allele, i.e. a β-catenin gene with exon 3
encoding serine and threonine residues flanked by LoxP sites [β-catenin
flox(ex3); hereafter designated as Catnb(ex3)fl/+]. Cre
recombinase-mediated excision leads to the expression of a stabilized,
constitutively active form of β-catenin
(Harada et al., 1999). We
observed that hair placodes and the dermal condensate expanded and that
embryonic epidermal keratinocytes displayed an HF-like differentiation in
K5-Cre Catnb(ex3)fl/+ mutant mice. Intriguingly, those phenotypes
were suppressed by introducing an additional conditional mutation: K5-Cre
Catnb(ex3)fl/+BmprIAfl/fl or K5-Cre
Catnb(ex3)fl/+Shhfl/-. These results demonstrate that
growth factor signal cross-talk under conditions of activated β-catenin
are mediated through Shh and Bmp signaling, and are the principal mechanisms
for regulating HF fate. The assessment of the Bmp(s) promoter activity and
analysis of Shh protein expression also provided clues to understand the
mechanisms of signal cross-talk during embryonic HF fate change.
MATERIALS AND METHODS
Mouse mutant alleles
The Catnb(ex3)fl/+, BmprIAfl/fl, Shhfl/fl
and Shhf/- alleles, and the keratin 5-Cre (K5-Cre) strain have been
described previously (Chiang et al.,
1996; Harada et al.,
1999; Mishina et al.,
2002; Tarutani et al.,
1997) (Jackson Laboratories Stock #004293). The BAT-lacZ
mouse containing a construct including the Tcf/Lef-binding sites has also been
described (Nakaya et al.,
2005). Sampling of dorsal skin specimens was performed between
embryonic day (E) 10.5 and E18.5. All animal experiments were approved by the
Animal Study Committee of the Kumamoto University School of Medicine.
|
Antibodies used were: keratin 1 (Covance PRB-165P), AE13 (AbCam), loricrin
(Covance PRB-145P), β-catenin (BD Bioscience), Ki67 (Novo Castra), Shh
(Santa Cruz H-160) and pSmad1/5/8 (Cell Signaling)
(Ahn et al., 2001). Secondary
antibodies were conjugated to Alexa Fluor 488 or 546 IgGs (Molecular
Probes/Invitrogen). X-gal staining was performed as described previously
(Haraguchi et al., 2007).
In situ hybridization for gene expression analysis
In situ hybridization analysis was performed on 8-µm paraffin sections
of embryonic back skin (Suzuki et al.,
2008) with probes for Bmp2, Shh, Lef1, Dkk1, Msx2 and
Pdgfra (kindly provided by B. L. Hogan, C. Shukunami, H. Clevers, U.
Rüther, Y. Liu and P. Soriano, respectively), Ptch1
(Goodrich et al., 1996),
Bmp4 (Jones et al.,
1991) and noggin (McMahon et
al., 1998). The Wnt10b probe was generated by PCR using
the following primers (F, 5'-GCG GGT CTC CTG TTC TTG GC-3'; R,
5'-AGA GGC GGC TGG TCT TGT TG-3').
Promoter assay with luciferase reporter activity
Bmp2 and Bmp4 promoter reporter constructs contain murine
gene fragments of 1725 bp (-410 to +1315) and 1828 bp (-1402 to +426),
respectively, in the reporter gene plasmid pGL3 basic (Invitrogen); numbers
are relative to the transcriptional start site. HaCaT cells were plated into
24-well plates at 2x105 cells per well in DMEM/10% FBS 24
hours prior to transfection. The reporter plasmids were co-transfected with a
control vector or with pcDNA3.1-His-mouse Gli2-delN2 (N-terminally truncated
Gli2 as a strong activator for hedgehog signaling)
(Sasaki et al., 1999), using
the TransFast Transfection Reagent (Promega), and luciferase activity was
measured using a Dual Luciferase Assay Kit (Promega)
(Nishida et al., 2008).
RESULTS AND DISCUSSION
Augmented β-catenin switches embryonic epidermal keratinocytes to the HF fate
To examine whether embryonic HF fate is determined through signaling
pathways regulated by β-catenin, conditional epidermal modulation of
β-catenin signaling was employed. Keratin 5-Cre (K5-Cre)-mediated
recombination and the expression kinetics of the constitutively active
β-catenin in the developing skin epidermis are shown in Fig. S1 in the
supplementary material.
K5-Cre Catnb(ex3)fl/+ mutant mice displayed scaly skin with
pillar-shaped comedo-like white spots in the embryonic epidermis
(Fig. 1B). Histological
analyses of the mutant embryos demonstrated a thickened epidermis without the
granular layers at E18.5 (Fig.
1C,D; the kinetics of the morphological alterations are shown in
Fig. S2 in the supplementary material). In addition, the mutant skin also
showed abnormal epidermal differentiation and denser cell layers in the upper
dermis (Fig. 1D).
Interestingly, the mutant epidermis showed follicular keratinization with
morphological trichilemma-type structures (see Fig. S3 in the supplementary
material). To determine the degree of such structural changes, we analyzed the
expression of terminal differentiation markers [K1 (Krt1 - Mouse Genome
Informatics) and loricrin] and hair shaft keratins that are specifically
recognized by the AE13 antibody (Lynch et
al., 1986). Expression of K1 and loricrin was dramatically reduced
in K5-Cre Catnb(ex3)fl/+ skin at E18.5
(Fig. 1E-H). By contrast, hair
shaft keratins were expressed broadly and strongly in the K5-Cre
Catnb(ex3)fl/+ mutant epidermis at E18.5, suggesting that augmented
β-catenin signaling induces HF-like differentiation
(Fig. 1E-J; the expression
kinetics are shown in Fig. S4 in the supplementary material).
Embryonic HF morphogenesis is governed by epithelial-mesenchymal
interactions between keratinocytes in the hair placode and fibroblasts in the
mesenchymal condensate (Hardy,
1992; Oro and Scott,
1998; Sengel,
1976). Signals from the hair placode induced the underlying
mesenchymal cells to condense (dermal condensate;
Fig. 1K; arrowheads). K5-Cre
Catnb(ex3)fl/+ mutant skin showed such dermal condensates
throughout the upper dermis at E16.5 (Fig.
1L, the kinetics of these morphological changes are shown in Fig.
S2 in the supplementary material). To further analyze the basis of the
excessive induction of HFs, the expression of hair placode markers (Bmps and
Shh) and dermal condensate markers [noggin, patched 1
(Ptch1) and Pdgfra] was examined. Bmp2 and
Bmp4 are expressed in the hair placode and in the underlying
mesenchymal condensate, respectively, in control skin
(Fig. 1M,O). Bmp2
expression was increased broadly in the mutant epidermis at E16.5
(Fig. 1N). Bmp4
expression was localized ectopically in the mutant epidermis at E15.0 with
expanded expression in later stages (Fig.
1P; data not shown). To investigate the extent of Bmp signaling,
the pSMAD levels were analyzed and were significantly increased in the mutant
epidermis and in the underlying mesenchyme compared with the control at E16.5
(Fig. 1Q,R; see also Fig. S5 in
the supplementary material). Shh expression was also broadly detected
in the mutant epidermis at E18.5 (Fig.
1T). The induced expression of Bmp2, Bmp4, pSMAD,
Shh and Wnt10b (another early placode marker) was already
observed at E11.5 (see Figs S5, S6 in the supplementary material). Dermal
condensate markers were expressed throughout the upper dermis in K5-Cre
Catnb(ex3)fl/+ mutant mice at E16.5
(Fig. 1U-Z). These results
suggest that augmented β-catenin signaling induces the excessive HF
induction and HF-like differentiation, leading to an HF fate.
|
). The
HF-like epidermal differentiation observed in K5-Cre Catnb(ex3)fl/+
mutant mice was suppressed by introduction of the double mutation at E18.5
(Fig. 2A-L). Loricrin and K1
expression were restored (Fig.
2E,F,H,I). In addition, the augmented AE13 epitope reactivity
observed in K5-Cre Catnb(ex3)fl/+ mutants was suppressed in the
double mutants, confirming the dramatic suppression of HF-like differentiation
(Fig. 2K,L). Msx2 is
one of the downstream target genes of Bmp signaling and regulates the
expression of Foxn1, which controls the transcription of hair keratin
genes (Ma et al., 2003;
Meier et al., 1999). The
expression of Msx2 was dramatically upregulated in K5-Cre
Catnb(ex3)fl/+ mutant epidermis, whereas its expression suppressed
in the double mutants at E16.5 (Fig.
2N,O). The Wnt/β-catenin pathway transcriptional effector
Lef1 regulates differentiation of the hair shaft
(Merrill et al., 2001). Its
increased expression was maintained in the double mutant epidermis at E16.5
(Fig. 2Q,R). We also found that
the region with the induced hair placode marker gene expression, which
includes that of Bmp2, remained in the K5-Cre
Catnb(ex3)fl/+BmprIAfl/fl mutant epidermis
(Fig. 2T,U; data not shown).
These results indicate that the pathway in which β-catenin is relayed by
Bmp signaling plays a principal role in inducing HF-like differentiation, but
not in the excessive induction of HFs (Fig.
4H).
Suppression of excessive HF induction by the conditional mutation of K5-Cre Catnb(ex3)fl/+Shhfl/-
One of the prominent phenotypes caused by augmented β-catenin is
aberrant HF patterning, the excessive hair placode induction with the
underlying dermal condensate (Fig.
1) (Narhi et al.,
2008; Zhang et al.,
2008). The excessive induction of HFs was not suppressed in K5-Cre
Cantb(ex3)fl/+BmprIAfl/fl mutant skin
(Fig. 2T,U).
Shh controls cell proliferation and formation of the dermal papilla
(Fuchs, 2007;
Millar, 2002;
Schmidt-Ullrich and Paus,
2005). Its overexpression leads to the induction of dermal
condensate during feather formation
(Ting-Berreth and Chuong,
1996) and its inhibition impairs dermal papilla formation
(Nanba et al., 2003). Shh has
been suggested to be regulated by the β-catenin signaling pathway
(Huelsken et al., 2001;
Zhang et al., 2008). Indeed,
expression of Shh was increased in the skin of K5-Cre
Cantb(ex3)fl/+ mice (Fig.
1T). To elucidate whether the excessive induction of HFs is
mediated by the Shh signaling pathway associated with augmented β-catenin
signaling, we analyzed K5-Cre Cantb(ex3)fl/+Shhfl/-
double mutant skin. Shh signaling was indeed decreased in K5-Cre
Cantb(ex3)fl/+Shhfl/- skin based on reduced
Ptch1 expression at E14.5 (see Fig. S7 in the supplementary
material). The number of hair placodes was increased in the K5-Cre
Catnb(ex3)fl/+ epidermis, spreading from the early-induced hair
placodes (Fig. S2 in the supplementary material; data not shown). The
excessive induction of HFs was suppressed in the double mutant skin based on
reduced hair placode marker gene expression (Bmp2 and
Wnt10b) and reduced Dkk1 expression at E16.5
(Fig. 3A-H). The expression of
Dkk1 is elevated in the dermis at sites of placode development in
normal embryos (Andl et al.,
2002). Dkk1 expression was strongly induced in the K5-Cre
Catnb(ex3)fl/+ dermis, but its expression was significantly
decreased in K5-Cre Cantb(ex3)fl/+Shhfl/- skin
throughout the upper dermis at E16.5 (Fig.
3H). The increased expression of dermal condensate markers (noggin
and Pdgfra) was also suppressed in K5-Cre
Cantb(ex3)fl/+Shhfl/- skin (data not shown).
Furthermore, the induction of HF-like differentiation was suppressed in the
K5-Cre Cantb(ex3)fl/+Shhfl/- mutant based on the reduced
immunostaining observed for AE13 at E16.5
(Fig. 3I,J). We also observed
decreased epidermal cell proliferation in K5-Cre
Cantb(ex3)fl/+Shhfl/- mutants compared with K5-Cre
Catnb(ex3)fl/+ mice at E18.5
(Fig. 3K,L). These results
suggested that Shh signaling is a crucial downstream pathway of β-catenin
signaling for the excessive induction of HFs with increased cell proliferation
(Fig. 4H).
|
;
Narhi et al., 2008). The
intensity of pSMAD staining in K5-Cre Cantb(ex3)fl/+ mutant skin
was suppressed in both the epidermis and the mesenchyme of K5-Cre
Cantb(ex3)fl/+Shhfl/- mutant skin at E16.5
(Fig. 4C, brackets). As for the
regulatory mechanisms controlling Bmp expression, we found several candidate
Lef/Tcf-binding sites in the 1.8-kb Bmp4 promoter and several
GLI-binding sites in the 1.7-kb Bmp2 promoter using rVISTA
bioinformatics analysis (Fig.
4D, yellow boxes; data not shown). Transient promoter assays
showed that the Bmp4 promoter was not regulated through stabilized
β-catenin signaling under the current experimental conditions (data not
shown), but revealed an increase of Bmp2 promoter activity caused by
Gli2 in vitro (Fig. 4D). In
fact, the current double mutant analyses on K5-Cre
Catnb(ex3)fl/+Shhfl/- skin showed suppression of the
increased Bmp2 expression, suggesting that the regulation of Bmp
signaling through Shh signaling is an essential molecular mechanism for the HF
fate change (Fig. 3C,D).
Increased Bmp2 expression, the intensity of pSMAD staining and AE13
immunostaining remained in early-induced HFs of the K5-Cre
Catnb(ex3)fl/+Shhfl/- epidermis
(Fig. 3;
Fig. 4C, outside of the
brackets). It has been shown that Shh signaling is not required for the
initiation of HF formation and that HF differentiation is not inhibited in Shh
mutant skin (Chiang et al.,
1999; St-Jacques et al.,
1998). Our current study indicates that Shh signaling is required
for the expansion of hair follicle fate by augmented β-catenin signaling,
although it is not required for either the initial specification of hair
placodes or the differentiation of early-induced HFs.
The regulation of HF space has been considered to be controlled by
diffusible molecules that either promote or repress follicular fate
(Jiang et al., 2004;
Mikkola and Millar, 2006;
Millar, 2002). Previously, it
was shown that Shh is one of the placode activators, while Bmps are generally
regarded as being placode inhibitors that mediate lateral inhibition, which is
known as the reaction-diffusion mechanism
(Jung et al., 1998). Studies
on chick embryonic skin suggested that Shh induces the expression of Bmps,
whereas Bmps suppress Shh expression during feather development
(Harris et al., 2005;
Jung et al., 1998). We further
analyzed the expression of Shh protein in K5-Cre
Cantb(ex3)fl/+BmprIAfl/fl skin. Interestingly, Shh
protein expression was both increased and expanded in K5-Cre
Cantb(ex3)fl/+BmprIAfl/fl mutant epidermis at E16.5
(Fig. 4E-G). Taken together,
the current results are in agreement with the reaction-diffusion mechanism,
via the cross-talk between the activator (Shh signaling) and the inhibitor
(Bmp signaling) implicated in the periodic patterning of HFs
(Fig. 4H)
(Jiang et al., 2004;
Jung et al., 1998).
|
Footnotes
We thank Drs Richard Behringer, Yuji Mishina, Brian Crenshaw, Junji Takeda, Cheng-Ming Chuong, Alex Joyner, Hiroshi Sasaki, Chi-Chung Hui, Brandon Wainwright, Anne M. Moon, Vincent J. Hearing, Shinji Takada, Pierre Chambon, Shinichi Miyagawa, Sawako Fujikawa, Shiho Miyaji, Yukiko Ogino, Ryuma Haraguchi, Liqing Liu and Ichiro Katayama for encouragement and suggestions. This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas, General Promotion of Cancer Research in Japan; a Grant-in-Aid for Scientific Research on Priority Areas, Mechanisms of Sex Differentiation; a Grant-in-Aid for Scientific Research (B) and for Young Scientists (B); the Global COE `Cell Fate Regulation Research and Education Unit'; and a Grant for Child Health and Development from the Ministry of Health, Labour and Welfare, Japan. Deposited in PMC for release after 12 months.
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