Cilia, Wnt signaling, and the cytoskeleton

Abstract

Primary cilia have recently been highlighted as key regulators in development and disease. This review focuses on current work demonstrating the broad role of cilia-related proteins in developmental signaling systems. Of particular consideration is the importance of the basal body region, located at the base of the cilium, in its role as a focal point for many signaling pathways and as a microtubule organizing center. As the cilium is effectively a microtubular extension of the cytoskeleton, investigating connections between the cilium and the cytoskeleton provides greater insight into signaling and cell function. Of the many signaling pathways associated with primary cilia, the most extensively studied in association with the cytoskeleton and cytoskeletal rearrangements are both canonical and non-canonical Wnt pathways. One of the key concepts currently emerging is a possible additional role for the traditionally 'cilia-related' proteins in other aspects of cellular processes. In many cases, disruption of such processes manifests at the level of the cilium. While the involvement of cilia and cilia-related proteins in signaling pathways is currently being unraveled, there is a growing body of evidence to support the notion that ciliary proteins are required not only for regulation of Wnt signaling, but also as downstream effectors of Wnt signaling. This review summarizes recent advances in our understanding of the involvement of cilia and basal body proteins in Wnt signaling pathways.

Figure 1

Ultrastructural depiction of the base of a generic mammalian cilium. The basal body (BB), derived from the mother centriole, nucleates the microtubule axoneme of the cilium. The basal body ends at the terminal plate (tp) and the transition fibers. The transition fibers are electron dense fibers at the base of the cilium connecting the ciliary axoneme to the plasma membrane. The transition zone (TZ) is characterized by the presence of the ciliary necklace on the ciliary membrane (not depicted) and Y-linkers, the end of which correspond with the basal plate (bp). In cilia that contain central microtubules, these emanate from the basal plate. The transition fibers and transition zone encompass the so-called 'ciliary gate', which possibly regulates protein entrance and exit. The fibers act as docking sites for intraflagellar transport particles and their motors, and could form part of a pore complex similar to the nuclear pores. The daughter centriole, connected to the basal body via an interconnecting fiber, and striated rootlet are also depicted. The ciliary pocket is an invagination of specialized cell membrane at the base of the cilium likely to be important for regulation of cilia composition.

Figure 2

Centrosome duplication during the cell cycle. (A) Centrosomes are comprised of two centrioles (mother and daughter) connected via an interconnecting fiber. The mother centriole has additional distal and sub distal appendages. The centrioles are surrounded by a matrix of proteins, the pericentriolar material (PCM). (B) During the cell cycle, each centriole (the original mother and daughter centriole) duplicates once, growing a new daughter centriole from their sides. The original mother centriole duplicates at a faster rate than the original daughter centriole. The original daughter centriole acquires additional appendages and thus becomes a new mother centriole. Mitosis separates the two centrosomes (duplicated centrioles) resulting in two cells each with a differentially aged mother centriole. Differences between these cells regarding cell fate and regulation are beginning to emerge.

Figure 3

Diagrammatic overview of Wnt involvement with the cytoskeleton. Transport of APC by kinesin motors plays an important role in microtubule stabilization, activation of protein kinases and cell polarization, which could all be regulated via the Gsk3β kinase. Phosphorylation of kinesins via kinases controls their sub-cellular localization and activity. Gsk3β is one of the central kinases predominantly associated with Wnt signaling and may influence many functions of kinesins through regulating cargo binding. Phospohrylation of APC by Gsk3β decreases the interaction of APC with microtubules, subsequently decreasing microtubule stability. Gsk3β could be considered a master regulator of kinesin control over MT dynamics, due to its ability to regulate a range of kinesins.

Figure 4

Diagram of Cdc42 regulation of cytoskeletal rearrangement. Cdc42 can control polarity via two separate pathways. Activation of Par6/aPKC inhibits GSK-3, which results in polarization of microtubules (MT). Rac-dependent polarization of the actin cytoskeleton is due to Pak activated βPIX.