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