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The Ciliopathy Gene Nphp-2 Functions in Multiple Gene Networks and Regulates

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The Ciliopathy Gene Nphp-2 Functions in Multiple Gene Networks and Regulates THE CILIOPATHY GENE NPHP-2 FUNCTIONS IN MULTIPLE GENE NETWORKS AND REGULATES CILIOGENESIS IN C. ELEGANS By SIMON ROBERT FREDERICK WARBURTON-PITT A dissertation submitted to the Graduate School – New Brunswick and The Graduate School of Biomedical Sciences Rutgers, The State University of New Jersey In partial fulfillment of the requirements For the degree of Doctor of Philosophy Graduate Program in Molecular Genetics and Microbiology Written under the direction of Maureen M. Barr, PhD And approved by New Brunswick, New Jersey January, 2015 © 2015 Simon Warburton-Pitt ALL RIGHTS RESERVED ABSTRACT OF THE DISSERTATION The ciliopathy gene nphp-2 functions in multiple gene networks and regulates ciliogenesis in C. elegans By SIMON ROBERT FREDERICK WARBURTON-PITT Dissertation Director: Maureen Barr Cilia are hair-like organelles that function as cellular antennae. Cilia are conserved across eukaryotes, and play a vital role in many biological processes including signal transduction, signal cascades, cell-cell signaling, cell orientation, cell-cell adhesion, motility, interorganismal communication, building extracellular matrix, and inducing fluid flow. In humans, cilia are present in a majority of tissue types, and cilia dysfunction can lead to a range of syndromic ciliopathies, including nephronopthisis (NPHP) and Meckel Syndrome (MKS). Cilia have a microtubule backbone, the axoneme, and are composed of multiple subcompartments, each with a specific function and composition: the transition zone (TZ) anchoring to the axoneme to the membrane, the doublet region extending from the TZ, and in some cilia types, the singlet region extending from the doublet region. The nematode C. elegans is a well-established model of cilia biology, and possesses cilia at the distal end of sensory dendrites. My work focused on exploring the role and function of nphp-2, the C. elegans ortholog of mammalian INVS/NPHP2, and the relationships between nphp-2, the TZ, and the doublet region. I found that TZ-associated genes can be grouped into ii two redundant genetic modules that interact with nphp-2 cell-type specific manner to regulate ciliogenesis and cilia placement. I also found that, like its ortholog Inversin (encoded by INVS), NPHP-2 localizes to the eponymous Inversin compartment, a subportion of the doublet region. nphp-2 genetically interacts with other doublet region-associated genes; like TZ-associated genes, these interactions can also be organized into two redundant genetic modules. The doublet region modules regulate many aspects of cilia biology, including ciliogenesis, cilia placement, microtubule patterning, tubulin post-translational modification, and doublet region composition. Additionally, I characterized a positive and a negative regulator of the doublet region modules. Together, these results help knit together data from mammalian models and C. elegans, and build a genetic framework between nphp-2 and genes from multiple ciliary compartments, pulling together what were disparate threads to lead us to a better understanding of cilia biology. iii Acknowledgments This thesis was a very long time coming, and I’d like to thank everyone who supported me during these years. Thanks to my funding sources NIH and Waksman Institute for generously funding my research. Thank you to my colleagues Jinghua Hu, Ollie Blacque, Corey Williams, and Michel Leroux for reagents, advice, and good conversation at meetings. A big thanks to my thesis committee for making time for me and helping my project through some sticky spots. A huge thanks to the Barr Lab past and present, which has made coming to work a fun and amazing experience; you guys are such an amazing group of people and I’ve learned and changed (hopefully for the better!) from knowing all of you. I also apologize for going on a bit too much about Jurassic Park, which none of you are likely ever going to want to see again. Thanks to my parents for never giving up on asking me when I was going to graduate, Julie for (PSST) never, ever letting it get too real, Brent for being a mathematical supergenius who introduced me to Elvira and drag queens, Becky for making me a Hippie, Natalia for endlessly (endless? :P) amazing conversation and hikes, dogs for existing, and Devin for being Devin. Also thanks to Square Enix, Namco, Bioware, Sony, Nintendo, Microsoft, the Vicar, Eddy and Patsy, Hyacinth, The Doctor, Matt Groening, Hideo Kojima, Stephen Baxter, Madonna, Lady Gaga, Exes, etc etc for keeping me sane and entertained. And thank you to Maureen, without whom none of this would ever have happened, who never ran out of patience for my antics, who trusts me, and who let me be my own scientist. Also, Devin again. iv Table of Contents Abstract Of The Dissertation ............................................................................................................ ii Acknowledgments........................................................................................................................... iv Table of Contents ............................................................................................................................. v Table of Figures ................................................................................................................................ x Table of Tables ............................................................................................................................... xii Chapter 1: Cilia Biology and the Inversin Compartment ................................................................. 1 1.1 – Introduction to cilia ............................................................................................................. 1 1.1.1 – Introduction ................................................................................................................. 1 1.1.2 – Abstract ........................................................................................................................ 1 1.2 – Brief Overview of Cilia Biology ............................................................................................ 2 1.2.1 – Cilia structure ............................................................................................................... 2 1.2.3 – The ciliary transition zone ............................................................................................ 8 1.2.4 – Ciliogenesis ................................................................................................................. 10 1.2.2 – Intraflagellar Transport .............................................................................................. 11 1.3 – Ciliopathies and cystic kidney disease .............................................................................. 13 1.4 – Characterizing the Inversin Compartment ........................................................................ 14 1.4.1 – Discovering a proximal ciliary compartment ............................................................. 14 1.4.2 – Defining the Proximal Cilium ...................................................................................... 16 1.4.3 – The Inversin Complex ................................................................................................. 17 1.4.4 – Establishing the Inv Compartment ............................................................................. 19 1.4.5 – Membrane Dynamics of the Inv Compartment ......................................................... 23 1.4.6 – Ultrastructure and microtubule dynamics ................................................................. 25 1.4.6.1 – Acetylation. ......................................................................................................... 26 1.4.6.2 – Glutamylation...................................................................................................... 27 1.5 – The Function of the Inversin Compartment ...................................................................... 29 1.5.1 – Signal Transduction and Amplification ...................................................................... 29 1.5.1.1 – Wnt signaling....................................................................................................... 29 1.5.1.2 – Hedgehog signaling. ............................................................................................ 32 1.5.1.3 – Other signaling pathways. ................................................................................... 33 v 1.5.2 – Ciliogenesis ................................................................................................................. 35 1.5.3 – Cilia Cycling ................................................................................................................ 35 1.5.4 – Cilia Length Regulation............................................................................................... 36 1.6 – Interactions between the InvC and other ciliary compartments ...................................... 38 1.6.1 – Interaction with the Transition Zone and Basal Body ................................................ 38 1.6.1.1 – Ciliogenesis. ......................................................................................................... 39 1.6.1.2 – Protein localization. ............................................................................................ 40 1.6.1.3 – Signaling pathways. ............................................................................................. 40 1.6.1.4 – Other TZ and InvC interactions. .........................................................................
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