Identification of transcriptional targets of Wnt/β-catenin signaling in dermal papilla cells of human scalp hair follicles: EP2 is a novel transcriptional target of Wnt3a
Introduction
The mammalian hair follicle contains dermal papilla and dermal sheath cells derived from the mesenchyme. It also contains epithelial cells of outer and inner root sheaths, matrix, and hair shaft, derived from the epithelium [1]. The post-natal hair follicle undergoes a cycle of growth (anagen), regression (catagen) and rest (telogen). The reciprocal interactions between the epithelium and mesenchyme are essential for post-natal hair growth as well as embryonic formation of hair [2]. Dermal papilla (DP) is encapsulated by the overlying epithelial cells during anagen and factors from DP are believed to cause epithelial cells to proliferate and differentiate to produce hair shaft [3]. Therefore, DP plays a key role in the regulation of hair growth and cycling.
Wnt glycoproteins regulate cellular homeostasis and development by binding to membrane Frizzled-LRP5/6 receptor complexes [4]. Wnt signaling can be specified into canonical pathway and noncanonical pathways. Canonical signaling causes accumulation of cytosolic β-catenin which then translocates to the nucleus, where β-catenin acts as a co-activator of T-cell factor (TCF) proteins to regulate gene expression. Noncanonical pathways lead to the activation of Rho, Rac, JNK and PKC, or to changes in the levels of Ca2+[4], [5].
It is recently reported that maintenance of Wnt signaling through the β-catenin pathway (canonical Wnt signaling) is required for hair-inducing activity of the dermal papilla and keeps DPCs in anagen-phase characteristics [6], [7]. It is also known that dermal papilla, in situ, is one of the sites of Wnt/β-catenin signaling [8]. Moreover, Wnt10b (a canonical Wnt) treatment accumulated β-catenin in DPCs in hair follicles cultured in vitro[9]. Hence, these results show that canonical Wnts act on DPCs. However, genome-wide screening of genes regulated by Wnt/β-catenin pathway in DPCs has not been reported. In this study, we identified transcriptional targets of the Wnt3a-regulated genes especially EP2 in human DPCs by microarrays.
Section snippets
Culture of DP cells and chemicals
Biopsy specimens were obtained from the occipital scalp regions of male patients with androgenic alopecia during hair transplantation at Kyungpook National University Hospital (Daegu, Korea) with patients’ consent. Dermal papillae were isolated from the bulbs of microdissected hair follicles, transferred onto plastic dishes coated with bovine type 1 collagen and cultured in Dulbecco's modified Eagle's medium (DMEM; Gibco BRL, Gaithersburg, MD, USA) supplemented with penicillin (100 U/ml),
Wnt3a stimulates β-catenin signaling in human DPCs
We first investigated whether cultured human DPCs in vitro respond to a canonical Wnt. Early passage primary DP cells (passage 2 and 3) were transiently transfected with either the β-catenin responsive TCF reporter plasmid (pTopflash) or corresponding negative control reporter (pFopflash) to assess the activity of β-catenin signaling by Wnt3a. We observed that Wnt3a significantly stimulated the transcriptional activity of pTopflash but not pFopflash (Fig. 1). Compared with the control, Topflash
Discussion
Recent studies showed that Wnt signaling through the β-catenin pathway that act on mouse dermal papilla cells (DPCs) enables hair follicles to keep growing [6], [7], [8], [9]. Kishimoto et al. [6] and Shimizu and Morgan [7] showed that Wnt3a and Wnt7a can play as inductive signals to maintain the mouse DPCs in an anagen state. In line with those reports, Maretto et al. revealed β-catenin activity in the DP of active anagen phase by using β-catenin-activated transgene, driving expression of
Acknowledgements
This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2008-331-E00228). This work was also supported by the Grant of the Korean Ministry of Education, Science and Technology (The Regional Core Research Program/Anti-aging and Well-being Research Center). This study was also supported by the Brain Korea 21 Project in 2010.
References (25)
The secret life of the hair follicle
Trends Genet
(1992)- et al.
Molecular control of epithelial–mesenchymal interactions during hair follicle cycling
J Investig Dermatol Symp Proc
(2003) - et al.
Wnt Signaling through the β-catenin pathway is sufficient to maintain, but not restore, anagen-phase characteristics of dermal papilla cells
J Invest Dermatol
(2004) - et al.
Effects of Wnt10b on hair shaft growth in hair follicle cultures
BBRC
(2007) - et al.
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription
Chem Biol
(2000) - et al.
Glycogen synthase kinase-3beta inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation
J Biol Chem
(2002) - et al.
Molecular aspects of the structures and functions of the prostaglandin E receptors
J Lipid Mediat Cell Signal
(1996) EP2 and EP4 prostanoid receptor signaling
Life Sci
(2003)- et al.
Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla
J Invest Dermatol
(2003) - et al.
Subcutaneous or topical administration of 16, 16 dimethyl prostaglandin E2 protects form radiation-induced alopecia in mice
Int J Radiat Oncol Biol Phys
(1992)
New topical agents for hair growth
Clin Dermatol
Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect
J Invest Dermatol
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These authors contributed equally to this work.