Background: Bone morphogenetic proteins (BMPs) play pivotal roles in the control of cell proliferation, differentiation, and apoptosis during development of many organs including skin. BMP signaling is activated by binding of the BMPs to BMP receptor complex that consists of type I and II BMP-receptors (BMPR-IA/IB, BMPR-II). In extracellular space, BMP signaling is modulated by BMP-antagonist noggin, which binds BMP-2/4/7 with high affinity and prevents their interaction with cell surface BMP receptors. BMP-Smad pathway is a major signaling mechanism that mediates BMP effects during development and postnatal growth. BMP-Smad pathway includes BMPRI-dependent phosphorylation of Smadl or Smad5 transcription factors, each of them then form the complex with Smad4 transcriptional co-activator followed by translocation into the nucleus to regulate transcription of BMP target genes. BMPs, noggin, Smad1 and Smad5 are broadly expressed in the hair follicle epithelium and mesenchyme during its development and cycling. However, due to embryonic lethality of the noggin, Smad1 or Smad5 knockout mice, their roles in the control of cell proliferation, differentiation and apoptosis in the hair follicle remain largely unknown. Based on our preliminary data, we hypothesize that spatial and temporal specificity of BMP effects in distinct hair follicle compartments is determined by noggin-dependent magnitude of signaling through BMP receptors and by differential recruitment of the Smad1 and Smad5 transcriptional regulators. Purpose: 1) Define the effects of general inhibition of BMP signaling in hair follicle epithelium and/or mesenchyme on hair follicle morphogenesis, cycling and hair pigmentation using noggin transgenic mice as models. 2) Delineate the roles of Smad1 and Smad5 transcriptional regulators in mediating the effects of BMP signaling on hair follicle morphogenesis and cycling using genetically engineered mice with loss of the Smad1 or Smad5 activity. 3) Identify the downstream targets of Smad1 and Smad5 that mediate cross-talk between the BMP-Smad pathway and other receptor signaling systems involved in regulating hair follicle morphogenesis, cycling and hair pigmentation. Significance: This study will provide further insights into the mechanisms of hair-growth regulation by BMPs, noggin. and Smad1/5 and will lead to the identification of new important target molecules that mediate the effects of BMP signaling on hair-follicle cells. Successful realization of this project will help in further understanding the pathobiology of different hair-loss conditions and may provide new strategies for their therapy using BMP agonists or antagonists.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ACTS (01))
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Baker, Carl
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Boston University
Schools of Medicine
United States
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Mardaryev, Andrei N; Liu, Bo; Rapisarda, Valentina et al. (2016) Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium. J Cell Biol 212:77-89
Botchkarev, Vladimir A (2015) Integration of the Transcription Factor-Regulated and Epigenetic Mechanisms in the Control of Keratinocyte Differentiation. J Investig Dermatol Symp Proc 17:30-2
Lewis, Christopher J; Mardaryev, Andrei N; Poterlowicz, Krzysztof et al. (2014) Bone morphogenetic protein signaling suppresses wound-induced skin repair by inhibiting keratinocyte proliferation and migration. J Invest Dermatol 134:827-837
Sharova, Tatyana Y; Poterlowicz, Krzysztof; Botchkareva, Natalia V et al. (2014) Complex changes in the apoptotic and cell differentiation programs during initiation of the hair follicle response to chemotherapy. J Invest Dermatol 134:2873-2882
Mardaryev, Andrei N; Gdula, Michal R; Yarker, Joanne L et al. (2014) p63 and Brg1 control developmentally regulated higher-order chromatin remodelling at the epidermal differentiation complex locus in epidermal progenitor cells. Development 141:101-11
Gdula, Michal R; Poterlowicz, Krzysztof; Mardaryev, Andrei N et al. (2013) Remodeling of three-dimensional organization of the nucleus during terminal keratinocyte differentiation in the epidermis. J Invest Dermatol 133:2191-201
Liu, Bo; Liu, Yuan-Feng; Du, Ya-Rui et al. (2013) Cbx4 regulates the proliferation of thymic epithelial cells and thymus function. Development 140:780-8
Botchkarev, Vladimir A; Gdula, Michal R; Mardaryev, Andrei N et al. (2012) Epigenetic regulation of gene expression in keratinocytes. J Invest Dermatol 132:2505-21
Mardaryev, Andrei N; Meier, Natalia; Poterlowicz, Krzysztof et al. (2011) Lhx2 differentially regulates Sox9, Tcf4 and Lgr5 in hair follicle stem cells to promote epidermal regeneration after injury. Development 138:4843-52
Fessing, Michael Y; Mardaryev, Andrei N; Gdula, Michal R et al. (2011) p63 regulates Satb1 to control tissue-specific chromatin remodeling during development of the epidermis. J Cell Biol 194:825-39

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