The ciliopathy gene nphp 2 functions in multiple gene networks and regulates ciliogenesis in c. elegans

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 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.Ph.D.Includes bibliographical referencesby Simon Warburton-Pit