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First published online 11 February 2009
doi: 10.1242/dev.030700
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Research Report |
Department of Developmental Biology, Division of Dermatology, Washington University School of Medicine, Box 8103, 660 South Euclid Avenue, St Louis, MO 63110, USA.
* Author for correspondence (e-mail: kopan{at}wustl.edu)
Accepted 21 January 2009
SUMMARY
Notch signaling plays an important role in hair follicle maintenance, and it has been suggested that Notch is also required for follicular fate selection by adult hair follicle stem cells in the bulge. Here we demonstrate that, on the contrary, Notch signaling in bi-potential bulge stem cells or their uncommitted descendents acts to suppress the epidermal fate choice, thus ensuring follicular fate selection. To examine the role of Notch signaling in adult hair follicle stem cells, we used a Krt1-15-CrePR1 transgenic mouse line to delete Rbpj or all Notch proteins specifically in the bulge stem cells. We conclusively determined that in the absence of Notch signaling, bulge stem cell descendents retain their capacity to execute the follicular differentiation program but fail to maintain it owing to their genetic deficiency. The defect in terminal differentiation caused the diversion of Notch-deficient hair follicles to epidermal cysts, and the presence of wild-type cells could not prevent this conversion. Importantly, our analysis revealed that a functional Notch signaling pathway was required to block bulge stem cells from migrating into, and assuming the fate of, interfollicular epidermis. Taken together, our findings yield detailed insight into the function of Notch signaling in hair follicle stem cells and reveal the mechanism of the replacement of Notch-deficient adult hair follicles by epidermal cysts.
Key words: Notch, Bulge, Fate selection, Stem cells, Mouse
INTRODUCTION
The mammalian hair follicle continuously cycles through three distinct
phases: (1) anagen of variable length (regenerative/proliferative phase); (2)
catagen, a short destructive phase during which the lower part of the hair
follicle containing the proliferating and keratogenous zones is removed; and
(3) telogen (resting phase) (Muller-Rover
et al., 2001
). The quiescent hair follicle stem cells reside in
the bulge located in the permanent part of the hair follicle near the arrector
pili muscle attachment site (Blanpain and
Fuchs, 2006; Cotsarelis et al.,
1990). During each hair cycle, a few bulge stem cells respond to
signals from dermal papillae and give rise to new progenitor cells that reside
in the hair matrix. This highly proliferative structure surrounds the dermal
papilla at the base of the bulb and generates the new anagen hair shaft
(Hardy, 1992;
Millar, 2002). Matrix cells
divide and differentiate into the outer root sheet (ORS), inner root sheet
(IRS), cuticle, cortex and medulla of the hair
(Legue and Nicolas, 2005). An
elaborate network of signaling pathways regulates hair follicle morphogenesis
and maintenance (Fuchs and Horsley,
2008; Millar,
2002). The Notch signaling pathway contributes to the maintenance
of the follicular structure but not to cell fate selection during hair
follicle morphogenesis (Pan et al.,
2004). In addition, Notch signaling ensures an optimal
proliferative environment in the matrix during first anagen by suppressing
Tgfβ and activating Kit ligand (Lee
et al., 2007).
Notch regulates keratinocyte proliferation, commitment and differentiation
decisions in intact skin and in culture
(Blanpain et al., 2006;
Lee et al., 2007;
Pan et al., 2004;
Rangarajan et al., 2001). In
response to ligand binding, Notch receptors undergo sequential proteolysis by
two enzymes (ADAM metalloprotease followed by 
-secretase) to release
the active Notch intracellular domain fragment (NICD), which translocates into
the nucleus, binds to Rbpj and nucleates the recruitment of a
transcription-activating complex (Lubman
et al., 2004). This overall scheme is termed `canonical' Notch
signaling. Part of Notch function in epidermal keratinocytes is mediated by a
poorly defined, Rbpj-independent signal
(Demehri et al., 2008;
Rangarajan et al., 2001).
Although Notch receptors do not function during hair germ cell induction or
cell fate acquisition within the embryonic hair follicle, they are required to
complete terminal differentiation in IRS cells. In the anagen hair follicle
bulb, three Notch receptors are expressed in partially overlapping domains
(Pan et al., 2004). Each
follicle is derived from two to four multi-potent bulge stem cells
(Jaks et al., 2008;
Kopan et al., 2002), which
give rise to oligo-lineage hair follicular progenitors
(Legue and Nicolas, 2005)
located adjacent to the dermal papilla in the matrix. Notch proteins are not
expressed in these oligo-lineage progenitors
(Kopan and Weintraub, 1993;
Pan et al., 2004;
Powell et al., 1998). Notch1
is expressed and activated in mitotically active IRS and cortex precursors
(Cai et al., 2009;
Pan et al., 2004), whereas
Notch2 and Notch3 are expressed in their postmitotic descendents, respectively
(Pan et al., 2004). In the
absence of Notch signaling, a hair shaft still forms and contains properly
positioned cells expressing markers for each fate
(Pan et al., 2004). However,
because IRS cells fail to properly adhere to each other, follicular
architecture cannot be maintained, leading to the transformation of these
aberrant hair follicles into epidermal cysts during the first anagen by
overproliferating ORS cells (Pan et al.,
2004).
Partial reduction in Notch signaling has also been associated with the
conversion of hair follicles to epidermal cysts in adults (see Fig. S1 in the
supplementary material) (Vauclair et al.,
2005; Yamamoto et al.,
2003). However, it is unclear whether the switch from a hair
follicle to an epidermal unit during the hair cycle in adult Notch-deficient
animals reflects (1) epidermal fate selection by Notch-deficient hair follicle
stem cells in the bulge or (2) terminal differentiation defects caused by loss
of Notch proteins in committed hair follicle progenitors that lead to aberrant
hair shaft formation and to conversion of the hair follicle into an epidermal
cyst. Previous studies have supported the former possibility by demonstrating
that mosaic loss of Notch signaling by Rbpj removal in hair follicles
results in reduced follicular regeneration during postnatal life owing to a
fate switch at the level of the Rbpj-deficient bulge stem cells
(Yamamoto et al., 2003). In
addition, fate mapping of the cells that have experienced Notch1 activation in
mice marks cells in the bulge (Vooijs et
al., 2007), consistent with a role for Notch1 in this
structure.
To differentiate between these possibilities, we used the inducible
stem-cell-specific Krt1-15-CrePR1 transgenic line
(Ito et al., 2005) to remove
Notch pathway components in hair follicle stem cells. We determined that Notch
signaling is not required for stem cells to select and execute the follicular
program; instead, it plays an inhibitory role in preventing bulge stem cells
from differentiating into epidermal cells. Therefore, our findings describe
the role of Notch signaling in adult hair follicle stem cells, where it acts
to ensure a follicular choice in bi-potential stem cells or in their
uncommitted descendents.
MATERIALS AND METHODS
Mice
We generated mouse strains lacking Notch signaling pathway components in
skin keratinocytes using the Msx2-Cre transgene
(Pan et al., 2004). For the
hair follicle stem cell studies, Krt1-15-CrePR1; Rbpjflox/flox;
Rosa26R (K15-RBP-jCKO), Krt1-15-CrePR1; Rbpjflox/+;
Rosa26R (control), Krt1-15-CrePR1; Notch1flox/flox;
Notch2flox/flox; Notch3–/–; Rosa26R
(K15-N1N2N3CKO), Krt1-15-CrePR1; Notch1flox/+;
Notch2flox/+; Notch3–/–; Rosa26R
(control), and Krt1-15-CrePR1; Notch1flox/flox; Rosa26R
(K15-N1CKO) were used (Ito et al.,
2005). The CrePR1 fusion protein may be leaky in the absence of
RU486 (Zhou et al., 2002);
however, examination of K15-RBP-jCKO or K15-N1N2N3CKO animals prior to
administration of RU486 revealed no evidence of gene deletion until after
P120. Therefore, we induced gene deletion at P50, well before this leaky
expression, in order to avoid any confounding effect. All mice were kept in
accordance with Washington University animal care regulations.
Lineage analysis
To induce Cre-mediated floxed gene deletion in the Krt1-15-CrePR1
system, mice were shaved and treated topically with 1% RU486 (Sigma, St Louis,
MO, USA) dissolved in 70% ethanol for 5 consecutive days, starting at the
beginning of the second telogen (
P50). A subgroup of animals was
depilated mechanically using the Hair Remover Wax Strip Kit (Del Laboratories,
Uniondale, NY, USA). At the indicated time points, dorsal skin was collected
and analyzed.
Histology and immunohistochemistry
For Hematoxylin and Eosin (H&E) staining, skin samples from various
mutant and wild-type animals were fixed in 4% paraformaldehyde in PBS, and
paraffin-embedded tissues were sectioned at 5 µm. Staining for
β-galactosidase activity (X-Gal staining) was performed on whole-mount
skin samples as described (Kopan et al.,
2002). Skin sections that were only X-Gal stained were
counterstained with Nuclear Fast Red (Vector Laboratories, Burlingame, CA,
USA). X-Gal-stained paraffin-embedded skin samples were used for
immunohistochemical analysis. Anti-hair follicle keratin (AE13) antibody (a
kind gift from Dr Tung-Tien Sun, New York University), anti-Rbpj antibody
(clone T6709, Institute of Immunology, Tokyo, Japan), anti-keratin 10 antibody
(Covance Research Products, Princeton, NJ, USA), anti-keratin 6 antibody
(Abcam, Cambridge, MA, USA), anti-loricrin antibody (Covance Research
Products), and anti-pan-leukocytic marker (CD45) (BD Biosciences Pharmingen,
San Diego, CA, USA) were used. After treatment with biotinylated secondary
antibody, HRP-conjugated streptavidin (Vectastain ABC Kit) and the DAB
Substrate Kit (Pierce, Rockford, IL, USA) were applied to visualize the
signal. No counterstaining was performed in immunohistochemical staining.
Immunofluorescence staining was conducted on paraffin-embedded skin samples
using a combination of the anti-keratin 10 and anti-loricrin antibodies.
Fluorochrome-conjugated secondary antibodies were used to visualize the
signals and DAPI nuclear stain was used as the counterstain.
RESULTS AND DISCUSSION
Notch signaling is not required for follicular fate determination of bulge stem cells
To directly examine the possibility that Notch is required for follicular
fate selection during hair regeneration, we used Krt1-15-CrePR1
transgenic mice (Ito et al.,
2005) to remove canonical Notch signaling specifically in bulge
stem cells in adulthood and determine whether bulge stem cells lacking Notch
signaling could produce daughters that choose the hair follicle fate.
Rbpj (Yamamoto et al.,
2003) deletion was induced by topical application of RU486 onto
the skin of postnatal day 50 (P50) Krt1-15-CrePR1;
Rbpjflox/flox; Rosa26R (K15-RBP-jCKO) mice at the beginning of
the second telogen. Fourteen days later, bulge cells were activated by
depilation, and 14 days after that we harvested the skin to examine the extent
of labeling within the regenerating hair follicles
(Fig. 1A). If Notch signaling
were required to select/execute the follicular fate, Rbpj-deficient
lacZ-positive cells would not be able to enter the follicular
program. Contrary to this prediction, X-Gal and antibody stainings
conclusively showed that blue Rbpj-deficient stem cells contributed
descendents to hair matrix progenitors as well as to hair follicle keratin
(AE13)-expressing cortex and cuticle cells
(Fig. 1B-D). To rule out the
possibility that depilation overcame the Notch deficiency, we repeated the
experiment by topically treating skin with RU486 and waited for the next
spontaneous anagen before harvesting the skin (see Fig. S2A in the
supplementary material). As seen with follicles regenerating after depilation,
hair follicles spontaneously entering anagen contained blue Rbpj-deficient
cells (see Fig. S2C in the supplementary material). Therefore, canonical Notch
signaling is not required for hair follicle fate selection by descendents of
bulge stem cells.
The analysis of a complete allelic series of mice lacking Notch signaling
components in their hair follicles revealed a tight inverse correlation
between Notch dosage in follicular keratinocytes and the level of hair
follicle distortion (Fig.
2A,B). Importantly, we noticed that Msx2-Cre/+;
Rbpjflox/flox hair follicles displayed a milder disruption at
P9 than that seen with total loss of Notch receptors or -secretase,
which led to epidermal keratin cyst formation during the first anagen
(Fig. 2A,B)
(Pan et al., 2004). Similar to
hair follicles retaining some Notch activity (Msx2-Cre/+;
Notch1flox/flox; Notch2flox/+;
Notch3+/–, or N1N2hN3hCKO) that formed epidermal cysts
only in the second anagen (Fig.
2C and see Fig. S1 in the supplementary material), Msx2-Cre/+;
Rbpjflox/flox follicles did not form epidermal cysts in the
first anagen and retained a recognizable follicular morphology at P9
(Fig. 2). As shown previously
(Demehri et al., 2008;
Rangarajan et al., 2001),
Rbpj-independent Notch signals contribute to hair follicle maintenance (see
Fig. S3 in the supplementary material). Thus, to address the concern that the
demonstrated ability of Rbpj-deficient bulge stem cells to choose a follicular
fate was preserved by Rbpj-independent Notch signal(s), we generated mice
lacking all Notch proteins in bulge stem cells (Krt1-15-CrePR1;
Notch1flox/flox; Notch2flox/flox;
Notch3–/–; Rosa26R, or K15-N1N2N3CKO). Following
the Cre induction/hair depilation protocol
(Fig. 1A), we showed that
Notch-deficient stem cell descendents were also fully capable of contributing
daughters to hair follicle structures (Fig.
1E). This finding demonstrates that neither arm of Notch signaling
is required for stem cells to choose the follicular fate.
Although Notch-deficient bulge stem cells (blue) migrated down and formed
anagen hair follicle progenitors and differentiated hair keratinocytes, the
defect in maintaining terminal differentiation resulted nonetheless in the
formation of aberrant hair shafts (Fig.
1B,E,F, Fig. 2 and
see Fig. S2C in the supplementary material). To study the long-term
consequences of Notch loss in bulge stem cells, we deleted Rbpj
(K15-RBP-jCKO) or Notch receptors (K15-N1N2N3CKO) by topical application of
RU486 onto the skin during the second telogen, and monitored the hair
phenotype over time by histological analyses
(Fig. 3A). In the absence of
Notch signaling, hair follicles eventually transformed into keratin 10- and
loricrin-positive epidermal cysts (Fig.
3B,C) following the destruction of anagen hair follicles in
K15-RBP-jCKO and K15-N1N2N3CKO skin. Such cysts were predominantly located
deep in the dermis (Fig. 3B).
Hair follicles are polyclonal, being derived from two to four stem cells
(Jaks et al., 2008;
Kopan et al., 2002), and not
all bulge cells undergo Notch gene/Rbpj deletion with our topical
application paradigm. Thus, most follicles are chimeric, containing
descendents of Notch/Rbpj-deficient stem cells as well as wild-type
descendents of stem cells that are Notch signaling competent. Importantly, a
significant number of keratin cyst-forming cells contained intact Notch
signaling, demonstrating that the `field effect' of aberrant hair shafts
formed by Notch/Rbpj-deficient keratinocytes was sufficient to set them on the
path to become epidermal cells (Fig.
3B). Accordingly, inactivation of Notch signaling in most bulges
resulted in complete alopecia within 10 weeks
(Fig. 3D), despite the presence
of many stem cells that did not experience Cre activation. Importantly,
K15-N1N2N3CKO hair loss was much more severe than that of RU486-treated
Krt1-15-CrePR1; Notch1flox/flox; Rosa26R (K15-N1CKO) mice
(Fig. 3D and see Fig. S4 in the
supplementary material). Considering that Notch3 is a null allele and
that Notch1/3-deficient hair follicles are indistinguishable from
Notch1-deficient hair follicles
(Pan et al., 2004), the
severity of the K15-N1N2N3CKO hair phenotype confirms that deletion of
Notch2 and Notch1 occurred in these
Notch3-deficient bulge cells. In conclusion, replacement of
Notch-deficient hair follicles by epidermal cysts is a secondary by-product of
terminal differentiation defects that cannot be rescued by normal cells, and
does not reflect a defective hair follicle fate-selection process. These
findings show that the function of Notch signaling during hair regeneration is
similar to its role during hair morphogenesis.
|
; Levy et al.,
2005), these observations demonstrate that Notch signaling acts to
prevent hair follicle stem cells or their uncommitted descendents from
randomly adopting the epidermal fate. How wounds reverse this block
(Ito et al., 2005) remains an
interesting question to be investigated.
|
|
|
),
neither arm of Notch signaling is required for follicular fate selection by
bulge stem cells. Instead, Rbpj-dependent Notch signals restrict bulge cells
(or their uncommitted, migratory descendents) to the follicular fate. In
addition to cells selecting the follicular fate, a substantial fraction of
Notch/Rbpj-deficient stem cells produce descendents that spontaneously choose
the epidermal fate and migrate upwards, joining the interfollicular epidermis
and producing epidermal cells deficient in terminal differentiation. The hair
follicles formed by Notch-deficient stem cells properly associate with dermal
papillae, produce a bulb expressing hair keratins, but fail to maintain the
identity of IRS cells and medulla (Pan et
al., 2004). Thus, both during hair follicle development and
regeneration, Notch contributes to terminal differentiation. The progressive
transformation of hair follicles to epidermal cysts caused by a stepwise
reduction in Notch dosage is the direct result of hair shaft disintegration
due to increasingly defective terminal differentiation.
This report identifies Notch signaling as a novel regulator of bulge stem
cell fate selection, acting to constrain this bi-potential cell to the hair
follicle fate. The ability of Notch/Rbpj-deficient stem cells to enter both
hair follicle and epidermal fates under the normal homeostatic state with
similar probability indicates a stochastic fate-selection process. This is in
contrast to the classical role for Notch in fate selection as seen in the fly
neuroectoderm, where a default fate (sensory organ precursor fate) is selected
by all Notch-deficient cells owing to the presence of a dominant factor
(Achaete-Scute proteins) (Simpson,
1997). The identities of molecules governing this stochastic
fate-selection process in mouse bulge stem cells, and the details of how Notch
constrains the fate choice, remain to be determined.
Footnotes
We thank Dr YongHua Pan and members of the Kopan laboratory for their suggestions during the course of this study; Mrs Tao Shen and Ahu Turkoz for genotyping and for assistance in caring for mice; Dr Larry Kedes for Hey1 antibody, Dr Gail Martin for providing Msx2-Cre mice, Dr Tom Gridley for N2flox/flox mice, and Dr Tasuku Honjo for Rbpjflox/flox mice. Special thanks to Dr George Cotsarelis for Krt1-15-CrePR1 mice and for numerous consultations during the course of this study. R.K. and S.D. were supported by NIH grant GM55479-10 from NIH/NIGMS. Deposited in PMC for release after 12 months.
Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/136/6/891/DC1
REFERENCES
Blanpain, C. and Fuchs, E. (2006). Epidermal
stem cells of the skin. Annu. Rev. Cell Dev. Biol.
22,339
-373.[CrossRef][Medline]
Blanpain, C., Lowry, W. E., Pasolli, H. A. and Fuchs, E.
(2006). Canonical notch signaling functions as a commitment
switch in the epidermal lineage. Genes Dev.
20,3022
-3035.
Cai, J., Lee, J., Kopan, R. and Ma, L. (2009).
Genetic interplays between Msx2 and Foxn1 are required for Notch1 expression
and hair shaft differentiation. Dev. Biol.
326,420
-430.[CrossRef][Medline]
Cotsarelis, G., Sun, T. T. and Lavker, R. M.
(1990). Label-retaining cells reside in the bulge area of
pilosebaceous unit: implications for follicular stem cells, hair cycle, and
skin carcinogenesis. Cell
61,1329
-1337.[CrossRef][Medline]
Demehri, S., Liu, Z., Lee, J., Lin, M. H., Crosby, S. D.,
Roberts, C. J., Grigsby, P. W., Miner, J. H., Farr, A. G. and Kopan, R.
(2008). Notch-deficient skin induces a lethal systemic
B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal
integrity. PLoS Biol. 6,e123
.[CrossRef][Medline]
Fuchs, E. and Horsley, V. (2008). More than one
way to skin. Genes Dev.
22,976
-985.
Hardy, M. H. (1992). The secret life of the
hair follicle. Trends Genet.
8, 55-61.[Medline]
Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. and
Birchmeier, W. (2001). beta-Catenin controls hair follicle
morphogenesis and stem cell differentiation in the skin.
Cell 105,533
-545.[CrossRef][Medline]
Ito, M., Liu, Y., Yang, Z., Nguyen, J., Liang, F., Morris, R. J.
and Cotsarelis, G. (2005). Stem cells in the hair follicle
bulge contribute to wound repair but not to homeostasis of the epidermis.
Nat. Med. 11,1351
-1354.[CrossRef][Medline]
Jaks, V., Barker, N., Kasper, M., van Es, J. H., Snippert, H.
J., Clevers, H. and Toftgard, R. (2008). Lgr5 marks cycling,
yet long-lived, hair follicle stem cells. Nat. Genet.
40,1291
-1299.[CrossRef][Medline]
Kopan, R. and Weintraub, H. (1993). Mouse
notch: expression in hair follicles correlates with cell fate determination.
J. Cell Biol. 121,631
-641.
Kopan, R., Lee, J., Lin, M. H., Syder, A. J., Kesterson, J.,
Crutchfield, N., Li, C. R., Wu, W., Books, J. and Gordon, J. I.
(2002). Genetic mosaic analysis indicates that the bulb region of
coat hair follicles contains a resident population of several active
multipotent epithelial lineage progenitors. Dev. Biol.
242, 44-57.[CrossRef][Medline]
Lee, J., Basak, J. M., Demehri, S. and Kopan, R.
(2007). Bi-compartmental communication contributes to the
opposite proliferative behavior of Notch1-deficient hair follicle and
epidermal keratinocytes. Development
134,2795
-2806.
Legue, E. and Nicolas, J. F. (2005). Hair
follicle renewal: organization of stem cells in the matrix and the role of
stereotyped lineages and behaviors. Development
132,4143
-4154.
Levy, V., Lindon, C., Harfe, B. D. and Morgan, B. A.
(2005). Distinct stem cell populations regenerate the follicle
and interfollicular epidermis. Dev. Cell
9, 855-861.[CrossRef][Medline]
Lubman, O. Y., Korolev, S. V. and Kopan, R.
(2004). Anchoring notch genetics and biochemistry; structural
analysis of the ankyrin domain sheds light on existing data. Mol.
Cell 13,619
-626.[CrossRef][Medline]
Millar, S. E. (2002). Molecular mechanisms
regulating hair follicle development. J. Invest.
Dermatol. 118,216
-225.[CrossRef][Medline]
Muller-Rover, S., Handjiski, B., van der Veen, C., Eichmuller,
S., Foitzik, K., McKay, I. A., Stenn, K. S. and Paus, R.
(2001). A comprehensive guide for the accurate classification of
murine hair follicles in distinct hair cycle stages. J. Invest.
Dermatol. 117,3
-15.[CrossRef][Medline]
Pan, Y., Lin, M. H., Tian, X., Cheng, H. T., Gridley, T., Shen,
J. and Kopan, R. (2004). gamma-secretase functions through
Notch signaling to maintain skin appendages but is not required for their
patterning or initial morphogenesis. Dev. Cell
7, 731-743.[CrossRef][Medline]
Powell, B. C., Passmore, E. A., Nesci, A. and Dunn, S. M.
(1998). The Notch signalling pathway in hair growth.
Mech. Dev. 78,189
-192.[CrossRef][Medline]
Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M., Mammucari,
C., Oh, H., Aster, J. C., Krishna, S., Metzger, D., Chambon, P. et al.
(2001). Notch signaling is a direct determinant of keratinocyte
growth arrest and entry into differentiation. EMBO J.
20,3427
-3436.[CrossRef][Medline]
Simpson, P. (1997). Notch signaling in
development. Perspect. Dev. Neurobiol.
4, 297-304.[Medline]
Vauclair, S., Nicolas, M., Barrandon, Y. and Radtke, F.
(2005). Notch1 is essential for postnatal hair follicle
development and homeostasis. Dev. Biol.
284,184
-193.[CrossRef][Medline]
Vooijs, M., Ong, C. T., Hadland, B., Huppert, S., Liu, Z.,
Korving, J., van den Born, M., Stappenbeck, T., Wu, Y., Clevers, H. et al.
(2007). Mapping the consequence of Notch1 proteolysis in vivo
with NIP-CRE. Development
134,535
-544.
Yamamoto, N., Tanigaki, K., Han, H., Hiai, H. and Honjo, T.
(2003). Notch/RBPJ signaling regulates epidermis/hair fate
determination of hair follicular stem cells. Curr.
Biol. 13,333
-338.[CrossRef][Medline]
Zhou, Z., Wang, D., Wang, X. J. and Roop, D. R.
(2002). In utero activation of K5.CrePR1 induces gene deletion.
Genesis 32,191
-192.[CrossRef][Medline]
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