Mammalian skin and its appendages function as the outermost barrier of the body to protect inner organs from environmental hazards and keep essential fluids within the body. Understanding molecular mechanisms that operate in skin development is an important prerequisite for future applications in regenerative medicine and for developing therapeutic treatment for human disease. Many regulatory mechanisms including cell signaling, cytoskeleton remodeling, transcriptional and epigenetic controls and post-transcriptional regulation have been implicated to have important roles in skin development. Among these mechanisms, microRNA-mediated post-transcriptional regulation exerts a widespread control over the output of the transcriptome. These noncoding RNA molecules broadly modulate a large number (~60% in mammals) of genes and play important roles in a wide range of biological processes. In mammalian skin, the critical functions of the miRNA pathway in embryonic and neonatal skin development have been well appreciated. However, individual microRNA functions and the underlying mechanisms remain poorly understood. In particular, microRNAs that play important roles in hair follicle morphogenesis are unknown despite extensive interests. To address this important issue, we propose to focus on the miR-200 family, a highly expressed microRNA family in the hair placode. Importantly, the loss of the miR-200 microRNAs in the skin leads to defective hair germ formation, consistent with their important functions in the skin. We will examine their roles in primary keratinocytes in vitro and in the hair placode in vivo (Aim 1 and 2). To provide mechanistic insights for their functions, we will apply biochemical purification of microRNAs and their associated mRNA targets to the WT and miR-200 knockout mice and identify miR-200-associated targets in a hair placode-specific manner. We will focus on comprehensively identifying important targets of miR-200 in regulation of cell proliferation, adhesion and migration as well as important signaling pathways in the skin. The long-term goal of this project is to elucidate individual microRNA functions and provide mechanistic insights to these molecules during skin development with a particular focus on hair morphogenesis. The knowledge gained from these studies will pave the way to manipulate microRNAs in neonatal skin progenitor cells for regenerative medicine and enhance our understanding for microRNAs' roles in skin cancer.
The microRNA pathway is required for mammalian skin development with particularly important functions in hair morphogenesis. In this proposal, I will investigate individual microRNA functions in the control of cell proliferation, adhesion and migration in the hair placode with genetically engineered mouse models. Knowledge gained from the proposed study will provide mechanistic understanding of post-transcriptional regulation in hair development.
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