Role of Primary Cilia-mediated Signaling in Development and Regeneration of the Meibomian Glands

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Dry eye disease (DED) is a common, multifactorial disease with a global prevalence ranging from 5 to 50%. Meibomian gland dysfunction (MGD) is considered the leading cause of DED. Meibomian glands (MG) are modified sebaceous glands which line the margin of the eyelid and secrete lipids at the ocular surface and participate to increase the stability of the tear film. MG are holocrine glands, which implies that they are continually renewed since they deliver their secretory product, called meibum, by apoptosis. Thus, regulation of MG stem cells is crucial to ensure proper function of MG. Currently, a significant hurdle in developing effective treatments to cure MGD is that the basic cellular mechanisms underlying the development and the stem cell- dependent maintenance of the MG are poorly understood. Interestingly, MG development shares similarities with the development of the pilosebaceous unit where primary cilia, and the hedgehog (HH) pathway play essential roles in hair follicle (HF) development and in maintaining a stem cell niche. Our preliminary data, using the mouse as a model system, mouse provide strong evidence that the cilium and the HH pathway play distinct roles during normal development of the MG. We found that the HH activity is high during early developmental stages of the MG. However, the number of HH responsive cells in the MG decreases as development progresses. In the adult, HH activity was detected in isolated cells of the acini and in the MG excretory duct. Moreover, we found that while inactivation of the HH pathway via SMO deletion abolishes or impairs the formation of MG, the deletion of IFT88, which prevents cilia formation, leads to hypertrophic MG. The objective of the proposed study is to elucidate the function of the primary cilium and the HH signaling pathway during the development and renewal of the MG with the long-term goal to identify new therapeutic targets to promote MG renewal. To address these issues, we have generated specific genetic tools and developed a 3D imaging analysis approach that will allow us to: a) To study the localization of ciliated and HH responsive cells in the context of Meibomian gland development and homeostasis. b) To elucidate the role of the HH pathway and the primary cilium during MG development and homeostasis. The outcome of this work will reveal the integrative role of primary cilia signaling necessary to achieve normal MG morphogenesis. Importantly, delineation of the cilia-related signaling cascades will enable the identification of new therapeutic strategies to treat DED.