UC San Diego

The primary cilium is a unique cellular organelle which in recent years has proven to be a surprisingly multifaceted structure. Primary cilia are ubiquitous ; they are present on almost all vertebrate cell types and play important regulatory roles in a growing number of signaling pathways. Recently, these tiny hair-like structures have been recognized for their functions in a variety of disorders termed "ciliopathies." The ciliopathies display a broad range of phenotypes that can affect a multitude of organs at varying times in a person's life. We now know that cilia are involved in a growing array of developmental and homeostatic functions which seem to be disrupted in the ciliopathies leading to a variety of phenotypes. Understanding these disorders will require a broader understanding of the vastly diverse biological functions of cilia. To study the role of primary cilia in two overlapping ciliopathies, Joubert syndrome and nephronophthisis, I have employed a mouse model with a deletion of the Ahi1 gene. AHI1 was the first identified gene mutated in patients with Joubert syndrome, a cerebellar development disorder. Joubert syndrome patients also often display a variety of other ciliopathy phenotypes which can include nephronophthisis, a cystic kidney disorder. Chapter 2 describes the kidney phenotype of Ahi1 mutant mice and the underlying Wnt defect. Ahi1 mutant mice display decreased canonical Wnt signaling which results in abnormal injury repair and a late-onset cyst pathology. Chapter 3 describes a unique signaling role for the primary cilium in regulation of Jouberin, the protein product of Ahi1, and its role in canonical Wnt signaling. The primary cilium seems to inhibit canonical Wnt signaling at multiple steps in the pathway including through sequestration of Jouberin and [beta]-catenin. Finally, Chapter 4 describes the cerebellar phenotype of Ahi1 null mice and the unique role of canonical Wnt signaling in cerebellar midline fusion. Overall, these results suggest that the primary cilium regulates canonical Wnt signaling in a variety of cellular contexts through a unique subcellular mechanism involving Jouberin