Rix, SM; (2012) The role of IFT80 in the molecular pathogenesis of Short Rib Polydactyly syndromes. Doctoral thesis , UCL (University of London).

Abstract

This thesis describes research into the developmental roles of IFT80, a protein component of intraflagellar transport (IFT) complex B. Mutations in IFT80 have been shown to be causative in both asphyxiating thoracic dystrophy (ATD) and short rib polydactyly (SRP) type III. Both diseases are autosomal recessive chondrodysplasias and share clinical and radiological similarities including shortening of the long bones and constriction of the thoracic cage. A genetrapped Ift80 line was used to investigate the role of Ift80 during murine development. This mouse model is a hypomorph due to low level wildtype transcript production. Hypomorphic levels of Ift80 are often embryonic lethal highlighting a key role for Ift80 in development. In cases where Ift80gt/gt mice survive to postnatal stages they phenocopy both ATD and SRP type III by exhibiting growth retardation, shortening of the long bones, constriction of the ribcage, and polydactyly. Analysis of the Hedgehog signalling pathway, a pathway shown to be abrogated in multiple models of IFT dysfunction, showed that reduction in Ift80 expression levels leads to reduced activity of the pathway. Processing of the key transcription factor Gli3 into its repressor form was seen to be altered leading to an abnormal activator/repressor ratio which may account for the observed pathway disruption. Widespread disruption to Wnt signalling, a pathway not commonly investigated in IFT models, was also seen in this line. This defective cellular signalling was not accompanied by the loss or malformation of cilia as seen in some knockout models of other IFT component genes. Phenotypes indicative of defects in cilia structure or function such as situs inversus, cystic renal disease and retinal degeneration were also not observed. SF-TAP and SILAC proteomics approaches were used to identify protein binding partners of IFT80. These suggested IFT80 associates primarily with a non-core subset of complex B proteins. A putative novel binding partner, NUDC was also identified in these screens. NUDC is known to play a role in dynein transport along microtubules, and was shown to localise to a region near the base of the cilium. A model is proposed in which an interaction between Ift80 and Nudc influences dynein entry into the cilium, and that reduced efficiency of this interaction in Ift80gt/gt mice causes a mild abrogation of retrograde transport leading to disrupted cellular signalling and thus to the skeletal phenotypes observed.

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