Dissertation/Thesis Abstract

Conservation and Divergence of Genetic Interactions and Functions Regulating Cilia and Embryogenesis
by Yee, Laura, Ph.D., University of California, San Francisco, 2015, 106; 3714076
Abstract (Summary)

Ciliopathies, diseases that arise from defective ciliary function, afflict many tissues to various degrees. However the genetic basis underlying the range of phenotypes is unclear. Two protein complexes at the ciliary transition zone are linked to the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP); the BBSome is a third complex linked to Bardet-Biedl syndrome. To model the complex inheritance of ciliopathies, we made double mutants between MKS, NPHP, and BBS genes, focusing on tctn-1, the C. elegans ortholog of the Tectonic family of ciliopathy genes. Loss of TCTN-1 or TCTN-1 and an MKS complex component does not disrupt ciliary structure. In contrast, loss of TCTN-1 and an NPHP complex component disrupts ciliary structure, as does loss of an NPHP and a BBS complex component. Thus, the MKS, NPHP and BBS complexes have overlapping ciliogenic functions in C. elegans. Similar genetic interactions that modify ciliopathy phenotypes are conserved in mammals, as mice mutant for both an MKS family gene and an NPHP family gene display exacerbated phenotypes compared to single mutants. Tctn1 and Bbs1 also show a synthetic genetic interaction in mammals. Together, our data support the hypothesis that multiple mutations within an individual organism may explain the expressivity observed in ciliopathy patients.

In addition, we investigated the role of Odr4 in mammals, a gene that is required for the localization of GPCRs to cilia in C. elegans. Preliminary studies demonstrate that Odr4 is required for embryonic development and binds to the Ufm1-specific protease, UfSP2.

Indexing (document details)
Advisor: Reiter, Jeremy F.
Commitee: Agard, David, Ashrafi, Kaveh, O'Farrell, Patrick
School: University of California, San Francisco
Department: Developmental Biology
School Location: United States -- California
Source: DAI-B 76/11(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Genetics, Cellular biology
Keywords: Cilia, Genetic interaction, Meckel syndrome, Nephronophthisis, Odr4, Tectonic
Publication Number: 3714076
ISBN: 9781321911190