Johanne Bay Mogensen:
Primary cilia are microtubule-based, non-motile, sensory organelles emerging in a single copy from the surface of most quiescent cells in vertebrates. They emanate from the centrosomal mother centriole and are assembled and maintained by a bidirectional transport process termed intraflagellar transport. Specific receptors, ion channels and downstream signaling components are localized along the cilium-centrosome axis, enabling the cilium to function as a hot spot for the balanced coordination of multiple signaling pathways to control cell cycle entry, differentiation and migration during embryonic development and in tissue homeostasis. Consequently defects in ciliary assembly and/or sensory function lead to a plethora of diseases and syndromic disorders termed ciliopathies, which include congenital heart defects, skeletal dysplasias, retinal degeneration, renal disease, cerebral anomalies, diabetes and tumorigenesis. A specialized gate at the proximal end of the cilium, the transition zone, maintains the specific ciliary protein composition as well as a specialized membrane lipid structure.
This dissertation includes two reviews on ciliary signaling (articles I and II) as well as two original articles (articles III and IV), which focuses on two specific signaling systems, conducted via the primary cilium; the Sonic hedgehog (SHH) and the Transforming growth factor β (TGFβ) signaling pathways. In article III we show that the motor protein, KIF13B, via its interaction with the transition zone protein NPHP4, is recruited to the ciliary base. The caveolae-enriched protein Caveolin-1 (CAV1) is concentrated at the transition zone of the cilium and depletion of KIF13B or NPHP4 dramatically alter this localization. In the absence of this specialized CAV1 microdomain, SHH-induced ciliary accumulation of Smoothened (SMO) and transcriptional of expression of GLI1 is impaired. We conclude that KIF13B and NPHP4 in concert establish a CAV1 rich membrane microdomain at the transition zone in primary cilia to regulate SHH signaling. In article IV we show that Tak1 and Tab2, two modulators of noncanonical TGFβ signaling operating through the NFκB pathway, localize to the primary cilium. Previous studies showed that mutations in TAB2 and TGFβ receptors lead to congenital heart disease, and we here demonstrate that Tab2 is upregulated during in vitro cardiomyogenesis and required for proper differentiation of mouse stem cells into cardiomyocytes. These results support the conclusion that Tab2 functions at the primary cilium to coordinate specified signaling events, which when defective may lead to congenital heart disease.
Collectively, the results presented in this PhD thesis provide new insights into the current understanding of the mechanisms underlying ciliary signal transduction. Further elucidation of this topic may contribute to knowledge leading to prevention and new therapeutic treatment opportunities against ciliopathies.