The primary cilium is an antenna-like structure that projects from the surface of virtually every cell in the human body where it receives sensory information from other cells and the environment. Defects in primary cilia cause human disease syndromes that impact many organ systems. The role of primary cilia in skin and hair follicle biology remains completely unexplored. Recent studies have shown that key proteins in the sonic hedgehog (Shh) and Wingless-Int (Wnt) signal transduction pathways localize to primary cilia, and primary cilia are required for their function. The Shh and Wnt pathways are essential for the development of the skin and hair follicles, and also for many other organ systems. Deregulation of these pathways is associated with several types of human cancer. Here we show that primary cilia are present on most cells of the skin and hair follicles of mice. We show that primary cilia are essential for normal skin and hair follicle development by performing conditional knockouts of two genes (Ift88 and Kif3a) that are required for the construction and function of cilia. Ablation of primary cilia from dermal mesenchyme cells caused hair follicle development to arrest at the germ hair stage, as is seen in mice with null mutations in Shh or Gli2, which is consistent with inactivation of the Shh pathway. However, ablation of primary cilia from epithelial cells in the skin and hair follicle resulted in a very unexpected phenotype (hyperproliferation of skin and sebaceous glands, epidermal downgrowths into the dermis, and altered hair alignment), which is consistent with overactivation of the Shh pathway and with alteration of the Wnt pathway. The focus of this application is to elucidate the molecular mechanisms underlying the role of primary cilia in the epithelial compartments of the skin and hair follicle. We propose that Ift88 and Kif3a may control the switch between cellular proliferation and differentiation in the epidermis by mediating and coordinating Shh and Wnt signaling in the primary cilium, the 2-catenin destruction complex, and the adherens junction.
In Aim 1 we will test the hypothesis that loss of cilia in the epidermis disrupts the balance between Gli activators and repressors in the Shh pathway, rather than completely blocking pathway activity, resulting in the hyperproliferative phenotype we observed.
In Aim 2 we will test the hypothesis that loss of Ift88 and Kif3a in the epidermis alters Wnt signaling by disrupting the formation of the 2-catenin destruction complex and adherens junctions, thereby disrupting the balance between canonical and non-canonical Wnt responsiveness.
In Aim 3 we probe the molecular mechanisms that underlie Ift88 and Kif3a function in the epidermis by conditionally ablating key components of the Shh and Wnt signaling pathways in mice with Ift88 (and cilia) ablated in the epidermis, and determine the impact of genetically altering these pathways on the epidermal phenotype. These studies will provide new insights into the function of epithelial primary cilia in morphogenetic signaling pathways that are central to skin and hair follicle development, and may lead to new treatments for skin cancer and hair loss. PROJECT NARRATIVE: The primary cilium is a small, antenna-like structure that protrudes from the surface of most all cells in the human body. Primary cilia are essential for receiving biochemical signals from neighboring cells and defects in primary cilia cause a variety of human disease syndromes. The focus of this work is to better understand the role of primary cilia in skin and hair follicle biology, which may lead to treatments for skin cancer and hair loss.
|Croyle, Mandy J; Lehman, Jonathan M; O'Connor, Amber K et al. (2011) Role of epidermal primary cilia in the homeostasis of skin and hair follicles. Development 138:1675-85|
|Schneider, Linda; Cammer, Michael; Lehman, Jonathan et al. (2010) Directional cell migration and chemotaxis in wound healing response to PDGF-AA are coordinated by the primary cilium in fibroblasts. Cell Physiol Biochem 25:279-92|
|Lehman, Jonathan M; Laag, Essam; Michaud, Edward J et al. (2009) An essential role for dermal primary cilia in hair follicle morphogenesis. J Invest Dermatol 129:438-48|
|Lehman, Jonathan M; Michaud, Edward J; Schoeb, Trenton R et al. (2008) The Oak Ridge Polycystic Kidney mouse: modeling ciliopathies of mice and men. Dev Dyn 237:1960-71|