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      Roles of Primary Cilia in the Developing Brain

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          Abstract

          Essential to development, primary cilia are microtubule-based cellular organelles that protrude from the surface of cells. Acting as cellular antenna, primary cilia play central roles in transducing or regulating several signaling pathways, including Sonic hedgehog (Shh) and Wnt signaling. Defects in primary cilia contribute to a group of syndromic disorders known as “ciliopathies” and can adversely affect development of the brain and other essential organs, including the kidneys, eyes, and liver. The molecular mechanisms of how defective primary cilia contribute to neurological defects, however, remain poorly understood. In this mini review, we summarize recent advances in understanding of the interactions between primary cilia and signaling pathways essential to cellular homeostasis and brain development.

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          Most cited references78

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          Patched1 regulates hedgehog signaling at the primary cilium.

          Primary cilia are essential for transduction of the Hedgehog (Hh) signal in mammals. We investigated the role of primary cilia in regulation of Patched1 (Ptc1), the receptor for Sonic Hedgehog (Shh). Ptc1 localized to cilia and inhibited Smoothened (Smo) by preventing its accumulation within cilia. When Shh bound to Ptc1, Ptc1 left the cilia, leading to accumulation of Smo and activation of signaling. Thus, primary cilia sense Shh and transduce signals that play critical roles in development, carcinogenesis, and stem cell function.
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            Primary Cilia and Mammalian Hedgehog Signaling.

            It has been a decade since it was discovered that primary cilia have an essential role in Hedgehog (Hh) signaling in mammals. This discovery came from screens in the mouse that identified a set of genes that are required for both normal Hh signaling and for the formation of primary cilia. Since then, dozens of mouse mutations have been identified that disrupt cilia in a variety of ways and have complex effects on Hedgehog signaling. Here, we summarize the genetic and developmental studies used to deduce how Hedgehog signal transduction is linked to cilia and the complex effects that perturbation of cilia structure can have on Hh signaling. We conclude by describing the current status of our understanding of the cell-type-specific regulation of ciliogenesis and how that determines the ability of cells to respond to Hedgehog ligands.
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              The mTOR pathway is regulated by polycystin-1, and its inhibition reverses renal cystogenesis in polycystic kidney disease.

              Autosomal-dominant polycystic kidney disease (ADPKD) is a common genetic disorder that frequently leads to renal failure. Mutations in polycystin-1 (PC1) underlie most cases of ADPKD, but the function of PC1 has remained poorly understood. No preventive treatment for this disease is available. Here, we show that the cytoplasmic tail of PC1 interacts with tuberin, and the mTOR pathway is inappropriately activated in cyst-lining epithelial cells in human ADPKD patients and mouse models. Rapamycin, an inhibitor of mTOR, is highly effective in reducing renal cystogenesis in two independent mouse models of PKD. Treatment of human ADPKD transplant-recipient patients with rapamycin results in a significant reduction in native polycystic kidney size. These results indicate that PC1 has an important function in the regulation of the mTOR pathway and that this pathway provides a target for medical therapy of ADPKD.
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                Author and article information

                Contributors
                Journal
                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                1662-5102
                14 May 2019
                2019
                : 13
                : 218
                Affiliations
                [1] 1Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology , Daejeon, South Korea
                [2] 2Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology , Daejeon, South Korea
                Author notes

                Edited by: Rosanna Parlato, University of Ulm, Germany

                Reviewed by: Elisabeth Traiffort, Institut National de la Santé et de la Recherche Médicale (INSERM), France; Esther Stoeckli, University of Zurich, Switzerland

                *Correspondence: Jeong Ho Lee, jhlee4246@ 123456kaist.ac.kr

                This article was submitted to Cellular Neurophysiology, a section of the journal Frontiers in Cellular Neuroscience

                Article
                10.3389/fncel.2019.00218
                6527876
                31139054
                7dd452c2-4e49-49bf-bb64-f541dd688686
                Copyright © 2019 Park, Jang and Lee.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 January 2019
                : 30 April 2019
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 104, Pages: 10, Words: 0
                Categories
                Neuroscience
                Mini Review

                Neurosciences
                primary cilia,wnt,mtor,autophagy,ciliopathy,fmcd
                Neurosciences
                primary cilia, wnt, mtor, autophagy, ciliopathy, fmcd

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