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Exploring Molecular Mechanisms Controlling Skin Homeostasis and Hair Growth. MicroRNAs in Hair-cycle-Dependent Gene Regulation, Hair Growth and Associated Tissue Remodelling. Item Type Thesis Authors Ahmed, Mohammed I. Rights <a rel="license" href="http://creativecommons.org/licenses/ by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by- nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http:// creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. Download date 02/10/2021 08:52:54 Link to Item http://hdl.handle.net/10454/5204 University of Bradford eThesis This thesis is hosted in Bradford Scholars – The University of Bradford Open Access repository. Visit the repository for full metadata or to contact the repository team © University of Bradford. This work is licenced for reuse under a Creative Commons Licence. Exploring Molecular Mechanisms Controlling Skin Homeostasis and Hair Growth MicroRNAs in Hair-cycle-Dependent Gene Regulation, Hair Growth and Associated Tissue Remodelling Mohammed Ikram AHMED BSc, MSc Submitted for the degree of Doctor of Philosophy Centre for Skin Sciences Division of Biomedical Sciences School of life Sciences University of Bradford 2010 Dedicated To my daughter Misba Ahmed and my Family II Abud-Darda (May Allah be pleased with him) reported; The messenger of Allah (PBUH) said, “He who follows a path in quest of knowledge, Allah will make the path of Jannah (heaven) easy to him. The angels lower their wings over the seeker of knowledge, being pleased with what he does. The inhabitants of the heavens and the earth and even the fish in the depth of the oceans seek forgiveness for him. The superiority of the learned man over the devout worshipper is like the full moon to the rest of the stars (i.e., in brightness). The learned are the heirs of the Prophets who bequeath neither dinar nor dirham (i.e., money) but only that of knowledge; and he acquires it, has in fact acquired an abundant portion.” Narrated by Abu Dawud and At-Tirmidhi (600AD) ..The key to success is to hold your head up high, walk straight, never waiver in your beliefs and praise those who have helped you on your way. Success comes to those who follow their dreams with determination and who take pride and risks on behalf of destiny. When you take up the challenge to help and inspire others and truly make a difference to their lives, therein lays true success and happiness. "If I have seen further (than certain other men) it is by standing upon the shoulders of giants." Sir Isaac Newton III Acknowledgement I am most grateful to almighty God (Allah s.w.t) for allowing me to accomplish all that I have achieved throughout my studies and life, and I thank the almighty for giving me the determination, self belief, strength and courage to complete this project. I would like to pay special praise, thanks and appreciation to my supervisor Dr Natalia Botchkareva for her invaluable support, encouragement and co- operation for whenever I approached her. I would like to also thank Professor Vladimir Botchkarev, Dr Andrei Mardaryev and Dr Michael Fessing. I am extremely indebted to their advice and assistance and I would not be in this position without their help and support. I would also like to thank my beloved parents, my wife and my family who have been very supportive of me. Finally, I wish to acknowledge and to thank my laboratory colleague Mr Michal Gdula for his help and support. I would also like to acknowledge my fellow PhD students for their encouraging words and continuous help. IV Abstract The hair follicle (HF) is a cyclic biological system that progresses through stages of growth, regression and quiescence, each being characterized by unique patterns of gene activation and silencing. MicroRNAs (miRNAs) are critically important for gene silencing and delineating their role in hair cycle may provide new insights into mechanisms of hair growth control and epithelial tissue remodelling. The aims of this study were: 1) To define changes in the miRNA profiles in skin during hair cycle-associated tissue remodelling; 2) To determine the role of individual miRNAs in regulating gene expression programs that drive HF growth, involution and quiescence; 3) and to explore the role of miRNAs in mediating the effects of BMP signalling in the skin. To address Aims 1 & 2, global miRNA expression profiling in the skin was performed and revealed marked changes in miRNAs expression during distinct stages of the murine hair cycle. Specifically, miR-31 markedly increased during anagen and decreased during catagen and telogen. Administration of antisense miR-31 inhibitor into mouse skin during the early- and mid-anagen phases of the hair cycle resulted in accelerated anagen development, and altered differentiation of hair matrix keratinocytes and hair shaft formation. Microarray, qRT-PCR and Western blot analyses revealed that miR-31 negatively regulates expression of Fgf10, the components of Wnt and BMP signalling pathways Sclerostin and BAMBI, and Dlx3 transcription factor, as well as selected keratin genes. Luciferase reporter assay revealed that Krt16, Krt17, Dlx3, and Fgf10 serve as direct miR-31 targets. In addition, miR-214 was identified as a potent inhibitor of the Wnt signalling pathway in the keratinocytes. Mutually exclusive expression patterns of miR-214 and β-catenin was observed during HF morphogenesis. MiR-214 decreases the expression of β-catenin and other components of Wnt signalling pathways c-myc, cyclin D1, and Pten in the keratinocytes. Luciferase reporter assay proved that β-catenin serves as a direct target of miR-214. In addition, miR-214 prevented translocation of β-catenin into the nucleus in response to the treatment with an activator of the Wnt signalling pathway lithium chloride, and abrogated the lithium-induced increase of the expression of the Wnt target gene V Axin2. This suggests that miR-214 may indeed be involved in regulation of skin development and regeneration at least in part, by controlling the expression of β-catenin and the activity of the Wnt signalling pathway. To address Aim 3, the role of miRNAs in mediating the effects of the bone morphogenetic protein (BMP) signalling in the skin was explored. MiRNAs were isolated from the primary mouse keratinocytes treated with BMP4 and processed for analysis of global miRNA expression using the microarray approach. Microarray and real-time PCR analysis revealed BMP4-dependent changes in the expression of distinct miRNAs, including miR-21, which expression was strongly decreased in the keratinocytes after BMP4 treatment. In contrast, miR-21 expression was substantially higher in the skin of transgenic mice over-expressing BMP antagonist Noggin. Transfection of the keratinocytes with miR-21 mimic revealed existence of two groups of the BMP target genes, which are differentially regulated by miR-21. Thus, this suggests a novel mechanism controlling the effects of BMP signalling in the keratinocytes. Thus, miRNAs play important roles in regulating gene expression programs in the skin during hair cycle. By targeting a number of growth regulatory molecules, transcription factors and cytoskeletal proteins, miRNAs are involved in establishing an optimal balance of gene expression in the keratinocytes required for the HF and skin homeostasis. Key words: MicroRNAs, Hair follicle, Growth control, Global miRNA expression, Keratin 16, Keratin 17, Dlx3, and Fgf10 VI Table of Contents Abstract ...................................................................................................... V Acknowledgment ...................................................................................... IV Contents ................................................................................................... VII List of Tables ........................................................................................... XII List of Figures ......................................................................................... XIII Abbreviations .......................................................................................... XV I. Introduction 1.1 Structure and Functions of the skin ............................................................ 1 1.1.1 Epidermis ................................................................................................ 2 1.1.2 Dermis .................................................................................................... 4 1.1.3 Skin appendages .................................................................................... 5 1.2 The Hair Follicle – Epidermal Derivative of the Skin .................................. 6 1.2.1 Importance and Functions ...................................................................... 6 1.3 Hair Follicle Anatomy ................................................................................. 9 1.4 Hair Shaft ................................................................................................. 12 1.5 The Inner Root Sheath ............................................................................. 13 1.6 The Outer Root Sheath ............................................................................ 16 1.7 Hair Follicle Stem Cells ............................................................................ 17 1.8 Hair Bulbs ................................................................................................ 21 1.9 Dermal
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