p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis

Genome organizer Satb1 is regulated by p63 and contributes to epidermal morphogenesis by remodeling chromatin structure and gene expression at the epidermal differentiation complex locus

Matrix Metalloproteinase-9 Is Involved in the Regulation of Hair Canal Formation.

noHair follicle (HF) morphogenesis is governed by a series of signals exchanged between the epidermal keratinocytes committed to HF-specific differentiation and the mesenchymal cells forming the follicular papilla (Schmidt-Ullrich and Paus, 2005). These interactions lead to the construction of the hair bulb, in which keratinocytes rapidly proliferate and differentiate into several cell populations forming the hair shaft and the inner root sheath. During the final steps of development, the HF elongates up to its maximal length and the hair shaft emerges through the epidermis through the hair canal that is formed at the distal portion of the HF epithelium (Schmidt-Ullrich and Paus, 2005). ...To elucidate a role for MMP-9 in the control of HF development and hair canal formation, its expression was studied by immunohistochemistry in cryosections of embryonic and postnatal skin of C57BL/6 mice (Sharov et al., 2003), and was correlated to the micro-anatomy of the developing hair canal depicted by high-resolution light microscopy, as described previously (Magerl et al., 2001). MMP-9 expression was not observed in the epidermis and developing HF placodes

Involvement of the Edar Signaling in the Control of Hair Follicle Involution (Catagen)

Ectodysplasin (Eda) and its receptor (Edar) are required for normal development of several ectodermal derivatives including hair follicles (HFs). Here, we show that during the murine hair cycle the expression of Eda A1, Edar, Edaradd, and TRAF6 transcripts are minimal in the resting phase and maximal during HF transition from active growth to regression (catagen). Eda A1 mRNA and Edar proteins were expressed in the hair matrix and outer and inner root sheaths of anagen HFs. During catagen, Eda A1 mRNA and Edar protein were expressed in the outer and inner root sheaths and later in the secondary hair germ. Catagen development accompanied by increased apoptosis in the outer root sheath was significantly accelerated in downless mice or after treatment of wild-type mice by a fusion protein that inhibits Edar signaling, compared with the corresponding controls. Microarray, real-time polymerase chain reaction, and immunohistochemical analyses of skin of downless mice revealed a strong decrease of expression of X-linked inhibitor of apoptosis protein (XIAP), compared with the controls, suggesting XIAP as a target for Edar signaling. Thus, our data demonstrate that in addition to its well-established role in HF morphogenesis, Edar signaling is also involved in hair cycle control and regulates apoptosis in HF keratinocytes during catagen

Complex Changes in the Apoptotic and Cell Differentiation Programs during Initiation of the Hair Follicle Response to Chemotherapy

NoChemotherapy has severe side effects in normal rapidly proliferating organs, such as hair follicles, and causes massive apoptosis in hair matrix keratinocytes followed by hair loss. To define the molecular signature of hair follicle response to chemotherapy, human scalp hair follicles cultured ex vivo were treated with doxorubicin (DXR), and global microarray analysis was performed 3 hours after treatment. Microarray data revealed changes in expression of 504 genes in DXR-treated hair follicles versus controls. Among these genes, upregulations of several tumor necrosis factor family of apoptotic receptors (FAS, TRAIL (tumor necrosis factor–related apoptosisinducing ligand) receptors 1/2), as well as of a large number of keratin-associated protein genes, were seen after DXR treatment. Hair follicle apoptosis induced by DXR was significantly inhibited by either TRAIL-neutralizing antibody or caspase-8 inhibitor, thus suggesting a previously unreported role for TRAIL receptor signaling in mediating DXR-induced hair loss. These data demonstrate that the early phase of the hair follicle response to DXR includes upregulation of apoptosis-associated markers, as well as substantial reorganization of the terminal differentiation programs in hair follicle keratinocytes. These data provide an important platform for further studies toward the design of effective approaches for the management of chemotherapy-induced hair loss

Bone Morphogenetic Protein Antagonist Noggin Promotes Skin Tumorigenesis via Stimulation of the Wnt and Shh Signaling Pathways

Bone morphogenetic proteins (BMPs) play pivotal roles in the regulation of skin development. To study the role of BMPs in skin tumorigenesis, BMP antagonist noggin was used to generate keratin 14-targeted transgenic mice. In contrast to wild-type mice, transgenic mice developed spontaneous hair follicle-derived tumors, which resemble human trichofolliculoma. Global gene expression profiles revealed that in contrast to anagen hair follicles of wild-type mice, tumors of transgenic mice showed stage-dependent increases in the expression of genes encoding the selected components of Wnt and Shh pathways. Specifically, expression of the Wnt ligands increased at the initiation stage of tumor formation, whereas expression of the Wnt antagonist and tumor suppressor Wnt inhibitory factor-1 decreased, as compared with fully developed tumors. In contrast, expression of the components of Shh pathway increased in fully developed tumors, as compared with the tumor placodes. Consistent with the expression data, pharmacological treatment of transgenic mice with Wnt and Shh antagonists resulted in the stage-dependent inhibition of tumor initiation, and progression, respectively. Furthermore, BMP signaling stimulated Wnt inhibitory factor-1 expression and promoter activity in cultured tumor cells and HaCaT keratinocytes, as well as inhibited Shh expression, as compared with the corresponding controls. Thus, tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways

Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata).

Alopecia areata (AA) is an autoimmune disorder of the hair follicle characterized by inflammatory cell infiltrates around actively growing (anagen) hair follicles. Substance P (SP) plays a critical role in the cutaneous neuroimmune network and influences immune cell functions through the neurokinin-1 receptor (NK-1R). To better understand the role of SP as an immunomodulatory neuropeptide in AA, we studied its expression and effects on immune cells in a C3H/HeJ mouse model for AA. During early stages of AA development, the number of SP-immunoreactive nerve fibers in skin is increased, compared to non-affected mice. However, during advanced stages of AA, the number of SP-immunoreactive nerves and SP protein levels in skin are decreased, whereas the expression of the SP-degrading enzyme neutral endopeptidase (NEP) is increased, compared to control skin. In AA, NK-1R is expressed on CD8+ lymphocytes and macrophages accumulating around affected hair follicles. Additional SP supply to the skin of AA-affected mice leads to a significant increase of mast cell degranulation and to accelerated hair follicle regression (catagen), accompanied by an increase of CD8+ cells-expressing granzyme B. These data suggest that SP, NEP, and NK-1R serve as important regulators in the molecular signaling network modulating inflammatory response in autoimmune hair loss

Bone morphogenetic protein signaling suppresses wound-induced skin repair by inhibiting keratinocyte proliferation and migration

Bone morphogenetic protein (BMP) signaling plays a key role in the control of skin development and postnatal remodeling by regulating keratinocyte proliferation, differentiation, and apoptosis. To study the role of BMPs in wound-induced epidermal repair, we used transgenic mice overexpressing the BMP downstream component Smad1 under the control of a K14 promoter as an in vivo model, as well as ex vivo and in vitro assays. K14-caSmad1 (transgenic mice overexpressing a constitutively active form of Smad1 under K14 promoter) mice exhibited retarded wound healing associated with significant inhibition of proliferation and increased apoptosis in healing wound epithelium. Furthermore, microarray and quantitative real-time reverse-transcriptase-PCR (qRT-PCR) analyses revealed decreased expression of a number of cytoskeletal/cell motility-associated genes including wound-associated keratins (Krt16, Krt17) and Myosin VA (Myo5a), in the epidermis of K14-caSmad1 mice versus wild-type (WT) controls during wound healing. BMP treatment significantly inhibited keratinocyte migration ex vivo, and primary keratinocytes of K14-caSmad1 mice showed retarded migration compared with WT controls. Finally, small interfering RNA (siRNA)-mediated silencing of BMPR-1B in primary mouse keratinocytes accelerated cell migration and was associated with increased expression of Krt16, Krt17, and Myo5a compared with controls. Thus, this study demonstrates that BMPs inhibit keratinocyte proliferation, cytoskeletal organization, and migration in regenerating skin epithelium during wound healing, and raises a possibility for using BMP antagonists for the management of chronic wounds