Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 309 (5736): 933-935

Copyright © 2005 by the American Association for the Advancement of Science

Stem Cell Depletion Through Epidermal Deletion of Rac1

Salvador Aznar Benitah,1 Michaela Frye,1 Michael Glogauer,2 Fiona M. Watt1*

Abstract: Mammalian epidermis is maintained by self-renewal of stem cells, but the underlying mechanisms are unknown. Deletion of Rac1, a Rho guanosine triphosphatase, in adult mouse epidermis stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc through p21-activated kinase 2 (PAK2) phosphorylation. We conclude that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and propose that Rac and Myc represent a global stem cell regulatory axis.

1 Keratinocyte Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
2 Faculty of Dentistry, University of Toronto, College Street, Toronto M5S 1A8, Canada.

* To whom correspondence should be addressed. E-mail: fiona.watt{at}

Small GTPase RhoE/Rnd3 Is a Critical Regulator of Notch1 Signaling.
Z. Zhu, K. Todorova, K. K. Lee, J. Wang, E. Kwon, I. Kehayov, H.-G. Kim, V. Kolev, G. P. Dotto, S. W. Lee, et al. (2014)
Cancer Res. 74, 2082-2093
   Abstract »    Full Text »    PDF »
The GEF Bcr activates RhoA/MAL signaling to promote keratinocyte differentiation via desmoglein-1.
A. D. Dubash, J. L. Koetsier, E. V. Amargo, N. A. Najor, R. M. Harmon, and K. J. Green (2013)
J. Cell Biol. 202, 653-666
   Abstract »    Full Text »    PDF »
Actin filament dynamics impacts keratinocyte stem cell maintenance.
D. Nanba, F. Toki, N. Matsushita, S. Matsushita, S. Higashiyama, and Y. Barrandon (2013)
EMBO Mol Med. 5, 640-653
   Abstract »    Full Text »    PDF »
CD98hc (SLC3A2) regulation of skin homeostasis wanes with age.
E. Boulter, S. Estrach, A. Errante, C. Pons, L. Cailleteau, F. Tissot, G. Meneguzzi, and C. C. Feral (2013)
J. Exp. Med. 210, 173-190
   Abstract »    Full Text »    PDF »
EZH2 Is Required for Breast and Pancreatic Cancer Stem Cell Maintenance and Can Be Used as a Functional Cancer Stem Cell Reporter.
L. E. van Vlerken, C. M. Kiefer, C. Morehouse, Y. Li, C. Groves, S. D. Wilson, Y. Yao, R. E. Hollingsworth, and E. M. Hurt (2013)
Stem Cells Trans Med 2, 43-52
   Abstract »    Full Text »    PDF »
Rac1 Controls Schwann Cell Myelination through cAMP and NF2/merlin.
L. Guo, C. Moon, K. Niehaus, Y. Zheng, and N. Ratner (2012)
J. Neurosci. 32, 17251-17261
   Abstract »    Full Text »    PDF »
RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3-dependent control of STAT1.
E. Pedersen, Z. Wang, A. Stanley, K. Peyrollier, L. M. Rosner, T. Werfel, F. Quondamatteo, and C. Brakebusch (2012)
J. Cell Sci. 125, 5379-5390
   Abstract »    Full Text »    PDF »
Governing epidermal homeostasis by coupling cell-cell adhesion to integrin and growth factor signaling, proliferation, and apoptosis.
G. Livshits, A. Kobielak, and E. Fuchs (2012)
PNAS 109, 4886-4891
   Abstract »    Full Text »    PDF »
A function for Rac1 in the terminal differentiation and pigmentation of hair.
K. Behrendt, J. Klatte, R. Pofahl, W. Bloch, N. Smyth, M. Tscharntke, T. Krieg, R. Paus, C. Niessen, C. Niemann, et al. (2012)
J. Cell Sci. 125, 896-905
   Abstract »    Full Text »    PDF »
Overabundance of Putative Cancer Stem Cells in Human Skin Keratinocyte Cells Malignantly Transformed by Arsenic.
Y. Sun, E. J. Tokar, and M. P. Waalkes (2012)
Toxicol. Sci. 125, 20-29
   Abstract »    Full Text »    PDF »
Direct binding of RalA to PKC{eta} and its crucial role in morphological change during keratinocyte differentiation.
Y. Shirai, S. Morioka, M. Sakuma, K.-i. Yoshino, C. Otsuji, N. Sakai, K. Kashiwagi, K. Chida, R. Shirakawa, H. Horiuchi, et al. (2011)
Mol. Biol. Cell 22, 1340-1352
   Abstract »    Full Text »    PDF »
Cell-Extracellular Matrix Interactions in Normal and Diseased Skin.
F. M. Watt and H. Fujiwara (2011)
Cold Spring Harb Perspect Biol 3, a005124
   Abstract »    Full Text »    PDF »
Arsenic, Stem Cells, and the Developmental Basis of Adult Cancer.
E. J. Tokar, W. Qu, and M. P. Waalkes (2011)
Toxicol. Sci. 120, S192-S203
   Abstract »    Full Text »    PDF »
Transcription factor E4F1 is essential for epidermal stem cell maintenance and skin homeostasis.
M. Lacroix, J. Caramel, P. Goguet-Rubio, L. K. Linares, S. Estrach, E. Hatchi, G. Rodier, G. Lledo, C. de Bettignies, A. Thepot, et al. (2010)
PNAS 107, 21076-21081
   Abstract »    Full Text »    PDF »
Unique and redundant functions of integrins in the epidermis.
C. Margadant, R. A. Charafeddine, and A. Sonnenberg (2010)
FASEB J 24, 4133-4152
   Abstract »    Full Text »    PDF »
CARM1 is required for proper control of proliferation and differentiation of pulmonary epithelial cells.
K. B. O'Brien, M. Alberich-Jorda, N. Yadav, O. Kocher, A. DiRuscio, A. Ebralidze, E. Levantini, N. J. L. Sng, M. Bhasin, T. Caron, et al. (2010)
Development 137, 2147-2156
   Abstract »    Full Text »    PDF »
Adhesion molecules in the stem cell niche - more than just staying in shape?.
V. Marthiens, I. Kazanis, L. Moss, K. Long, and C. ffrench-Constant (2010)
J. Cell Sci. 123, 1613-1622
   Abstract »    Full Text »    PDF »
Dose and context dependent effects of Myc on epidermal stem cell proliferation and differentiation.
M. A. Berta, C. M. Baker, D. L. Cottle, and F. M. Watt (2009)
EMBO Mol Med. 2, 16-25
   Abstract »    Full Text »    PDF »
Regulation of lymphatic-blood vessel separation by endothelial Rac1.
G. D'Amico, D. T. Jones, E. Nye, K. Sapienza, A. R. Ramjuan, L. E. Reynolds, S. D. Robinson, V. Kostourou, D. Martinez, D. Aubyn, et al. (2009)
Development 136, 4043-4053
   Abstract »    Full Text »    PDF »
Ovol2 Suppresses Cell Cycling and Terminal Differentiation of Keratinocytes by Directly Repressing c-Myc and Notch1.
J. Wells, B. Lee, A. Q. Cai, A. Karapetyan, W.-J. Lee, E. Rugg, S. Sinha, Q. Nie, and X. Dai (2009)
J. Biol. Chem. 284, 29125-29135
   Abstract »    Full Text »    PDF »
Necl2 regulates epidermal adhesion and wound repair.
A. Giangreco, K. B. Jensen, Y. Takai, J. Miyoshi, and F. M. Watt (2009)
Development 136, 3505-3514
   Abstract »    Full Text »    PDF »
Impact of Rac1 and Cdc42 Signaling during Early Herpes Simplex Virus Type 1 Infection of Keratinocytes.
P. Petermann, I. Haase, and D. Knebel-Morsdorf (2009)
J. Virol. 83, 9759-9772
   Abstract »    Full Text »    PDF »
Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function.
M. Haruta, R. A. Bush, S. Kjellstrom, C. Vijayasarathy, Y. Zeng, Y.-Z. Le, and P. A. Sieving (2009)
PNAS 106, 9397-9402
   Abstract »    Full Text »    PDF »
An Activating {beta}1 Integrin Mutation Increases the Conversion of Benign to Malignant Skin Tumors.
M. Ferreira, H. Fujiwara, K. Morita, and F. M. Watt (2009)
Cancer Res. 69, 1334-1342
   Abstract »    Full Text »    PDF »
RhoE Is Required for Keratinocyte Differentiation and Stratification.
T. Liebig, J. Erasmus, R. Kalaji, D. Davies, G. Loirand, A. Ridley, and V. M.M. Braga (2009)
Mol. Biol. Cell 20, 452-463
   Abstract »    Full Text »    PDF »
Building Epithelial Tissues from Skin Stem Cells.
E. Fuchs and J.A. Nowak (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Lamellar Bodies of Human Epidermis: Proteomics Characterization by High Throughput Mass Spectrometry and Possible Involvement of CLIP-170 in their Trafficking/Secretion.
A.-A. Raymond, A. G. de Peredo, A. Stella, A. Ishida-Yamamoto, D. Bouyssie, G. Serre, B. Monsarrat, and M. Simon (2008)
Mol. Cell. Proteomics 7, 2151-2175
   Abstract »    Full Text »    PDF »
Kazrin regulates keratinocyte cytoskeletal networks, intercellular junctions and differentiation.
L. M. Sevilla, R. Nachat, K. R. Groot, and F. M. Watt (2008)
J. Cell Sci. 121, 3561-3569
   Abstract »    Full Text »    PDF »
Arsenic Exposure In utero Exacerbates Skin Cancer Response in Adulthood with Contemporaneous Distortion of Tumor Stem Cell Dynamics.
M. P. Waalkes, J. Liu, D. R. Germolec, C. S. Trempus, R. E. Cannon, E. J. Tokar, R. W. Tennant, J. M. Ward, and B. A. Diwan (2008)
Cancer Res. 68, 8278-8285
   Abstract »    Full Text »    PDF »
Integrins control the positioning and proliferation of follicle stem cells in the Drosophila ovary.
A. M. O'Reilly, H.-H. Lee, and M. A. Simon (2008)
J. Cell Biol. 182, 801-815
   Abstract »    Full Text »    PDF »
Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation.
H. Stachelscheid, H. Ibrahim, L. Koch, A. Schmitz, M. Tscharntke, F. T. Wunderlich, J. Scott, C. Michels, C. Wickenhauser, I. Haase, et al. (2008)
EMBO J. 27, 2091-2101
   Abstract »    Full Text »    PDF »
c-myc in the hematopoietic lineage is crucial for its angiogenic function in the mouse embryo.
C. He, H. Hu, R. Braren, S.-Y. Fong, A. Trumpp, T. R. Carlson, and R. A. Wang (2008)
Development 135, 2467-2477
   Abstract »    Full Text »    PDF »
Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function.
N. C. Dubois, C. Adolphe, A. Ehninger, R. A. Wang, E. J. Robertson, and A. Trumpp (2008)
Development 135, 2455-2465
   Abstract »    Full Text »    PDF »
Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages.
A. C. Azim, H. Cao, X. Gao, M. Joo, A. B. Malik, R. B. van Breemen, R. T. Sadikot, G. Park, and J. W. Christman (2007)
Am J Physiol Lung Cell Mol Physiol 293, L668-L673
   Abstract »    Full Text »    PDF »
pak2a mutations cause cerebral hemorrhage in redhead zebrafish.
D. A. Buchner, F. Su, J. S. Yamaoka, M. Kamei, J. A. Shavit, L. K. Barthel, B. McGee, J. D. Amigo, S. Kim, A. W. Hanosh, et al. (2007)
PNAS 104, 13996-14001
   Abstract »    Full Text »    PDF »
Metabolic homeostasis and tissue renewal are dependent on {beta}1,6GlcNAc-branched N-glycans.
P. Cheung, J. Pawling, E. A Partridge, B. Sukhu, M. Grynpas, and J. W Dennis (2007)
Glycobiology 17, 828-837
   Abstract »    Full Text »    PDF »
A system-wide analysis of differentially expressed genes in ectopic and eutopic endometrium.
J. D. Wren, Y. Wu, and S.-W. Guo (2007)
Hum. Reprod. 22, 2093-2102
   Abstract »    Full Text »    PDF »
C/EBP{delta} regulates cell cycle and self-renewal of human limbal stem cells.
V. Barbaro, A. Testa, E. Di Iorio, F. Mavilio, G. Pellegrini, and M. De Luca (2007)
J. Cell Biol. 177, 1037-1049
   Abstract »    Full Text »    PDF »
Conditional targeting of plectin in prenatal and adult mouse stratified epithelia causes keratinocyte fragility and lesional epidermal barrier defects.
R. Ackerl, G. Walko, P. Fuchs, I. Fischer, M. Schmuth, and G. Wiche (2007)
J. Cell Sci. 120, 2435-2443
   Abstract »    Full Text »    PDF »
Double Duty for Rac1 in Epidermal Wound Healing.
C. M. DiPersio (2007)
Sci. STKE 2007, pe33
   Abstract »    Full Text »    PDF »
Impaired epidermal wound healing in vivo upon inhibition or deletion of Rac1.
M. Tscharntke, R. Pofahl, A. Chrostek-Grashoff, N. Smyth, C. Niessen, C. Niemann, B. Hartwig, V. Herzog, H. W. Klein, T. Krieg, et al. (2007)
J. Cell Sci. 120, 1480-1490
   Abstract »    Full Text »    PDF »
Evidence for a stem cell hierarchy in the adult human breast.
R. Villadsen, A. J. Fridriksdottir, L. Ronnov-Jessen, T. Gudjonsson, F. Rank, M. A. LaBarge, M. J. Bissell, and O. W. Petersen (2007)
J. Cell Biol. 177, 87-101
   Abstract »    Full Text »    PDF »
Destabilized Adhesion in the Gastric Proliferative Zone and c-Src Kinase Activation Mark the Development of Early Diffuse Gastric Cancer.
B. Humar, R. Fukuzawa, V. Blair, A. Dunbier, H. More, A. Charlton, H. K. Yang, W. H. Kim, A. E. Reeve, I. Martin, et al. (2007)
Cancer Res. 67, 2480-2489
   Abstract »    Full Text »    PDF »
Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCK{alpha} kinases.
K. Lefort, A. Mandinova, P. Ostano, V. Kolev, V. Calpini, I. Kolfschoten, V. Devgan, J. Lieb, W. Raffoul, D. Hohl, et al. (2007)
Genes & Dev. 21, 562-577
   Abstract »    Full Text »    PDF »
Rac1 GTPase Regulates Cell Genomic Stability and Senescence.
M. Debidda, D. A. Williams, and Y. Zheng (2006)
J. Biol. Chem. 281, 38519-38528
   Abstract »    Full Text »    PDF »
Regulation of epidermal homeostasis and repair by phosphoinositide 3-kinase.
S. Pankow, C. Bamberger, A. Klippel, and S. Werner (2006)
J. Cell Sci. 119, 4033-4046
   Abstract »    Full Text »    PDF »
Rac1 Is Crucial for Hair Follicle Integrity but Is Not Essential for Maintenance of the Epidermis.
A. Chrostek, X. Wu, F. Quondamatteo, R. Hu, A. Sanecka, C. Niemann, L. Langbein, I. Haase, and C. Brakebusch (2006)
Mol. Cell. Biol. 26, 6957-6970
   Abstract »    Full Text »    PDF »
Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence.
K. B. Jensen and F. M. Watt (2006)
PNAS 103, 11958-11963
   Abstract »    Full Text »    PDF »
Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin.
L. Williamson, N. A. Raess, R. Caldelari, A. Zakher, A. de Bruin, H. Posthaus, R. Bolli, T. Hunziker, M. M. Suter, and E. J. Muller (2006)
EMBO J. 25, 3298-3309
   Abstract »    Full Text »    PDF »
Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1.
L. Moldovan, K. Mythreye, P. J. Goldschmidt-Clermont, and L. L. Satterwhite (2006)
Cardiovasc Res 71, 236-246
   Abstract »    Full Text »    PDF »
Rac1 links integrin-mediated adhesion to the control of lactational differentiation in mammary epithelia.
N. Akhtar and C. H. Streuli (2006)
J. Cell Biol. 173, 781-793
   Abstract »    Full Text »    PDF »
Cottontail Rabbit Papillomavirus E8 Protein Is Essential for Wart Formation and Provides New Insights into Viral Pathogenesis.
M. Nonnenmacher, J. Salmon, Y. Jacob, G. Orth, and F. Breitburd (2006)
J. Virol. 80, 4890-4900
   Abstract »    Full Text »    PDF »
Role of LIM Kinases in Normal and Psoriatic Human Epidermis.
M. Honma, S. A. Benitah, and F. M. Watt (2006)
Mol. Biol. Cell 17, 1888-1896
   Abstract »    Full Text »    PDF »
Stem cells and their niches..
K. A. Moore and I. R. Lemischka (2006)
Science 311, 1880-1885
   Abstract »    Full Text »    PDF »
Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin..
X. Wu, F. Quondamatteo, T. Lefever, A. Czuchra, H. Meyer, A. Chrostek, R. Paus, L. Langbein, and C. Brakebusch (2006)
Genes & Dev. 20, 571-585
   Abstract »    Full Text »    PDF »
Microscale technologies for tissue engineering and biology.
A. Khademhosseini, R. Langer, J. Borenstein, and J. P. Vacanti (2006)
PNAS 103, 2480-2487
   Abstract »    Full Text »    PDF »
DEVELOPMENTAL BIOLOGY: Rac1 Up for Epidermal Stem Cells.
G. P. Dotto and G. Cotsarelis (2005)
Science 309, 890-891
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882