Sending mixed signals: Cilia-dependent signaling during development and disease

Abstract

Molecular signals are the guiding force of development, imparting direction upon cells to divide, migrate, differentiate, etc. The mechanisms by which a cell can receive and transduce these signals into measurable actions remains a 'black box' in developmental biology. Primary cilia are ubiquitous, microtubule-based organelles that dynamically extend from a cell to receive and process molecular and mechanical signaling cues. In the last decade, this organelle has become increasingly intriguing to the research community due to its ability to act as a cellular antenna, receive and transduce molecular stimuli, and initiate a cellular response. In this review, we discuss the structure of primary cilia, emphasizing how the ciliary components contribute to the transduction of signaling pathways. Furthermore, we address how the cilium integrates these signals and conveys them into cellular processes such as proliferation, migration and tissue patterning. Gaining a deeper understanding of the mechanisms used by primary cilia to receive and integrate molecular signals is essential, as it opens the door for the identification of therapeutic targets within the cilium that could alleviate pathological conditions brought on by aberrant molecular signaling.

Keywords: Hedgehog; Migration; Pdgf; Primary cilia; Proliferation; Wnt.

Figure 1. Cilia and their structure

Heterogeneity in ciliary structure. (A) Nodal cilia with either a 9+0 or 9+2 microtubule arrangement (inset), (B) primary cilia with a 9+0 microtubule arrangement (inset) and (C) airway cilia with a 9+2 microtubule structure (inset). (D) The detailed structure of a primary cilia, schematizing four main components: the basal body, transition zone, axoneme, and ciliary membrane.

Figure 2. Cilia-dependent Hh signaling

Activity of Hh pathway components in the (A) presence and (B) absence of Shh. (C) Loss of Inpp5e dampens the ability of the cilium to transduce a Shh signal, thus rendering the cilia “desensitized”. (D) Loss of EvC/EvC2 prevents Gli2/3 dissociation from Sufu, thus preventing transcription of downstream targets and generating a cilium “desensitized” to a Shh signal.

Figure 3. Hypothesized cilia-dependent Wnt signaling

(A) Hypothesized (and controversial) activity of Wnt pathway components in the (A) presence and (B) absence of Wnt. (C) Loss of Kif3a causes increased translocation of β-catenin to the nucleus and increased target gene expression, thus “sensitizing” the cell to Wnt signaling.

Figure 4. Cilia-dependent Pdgfrα signaling

(A) Pdgfrα localizes to the membrane of the primary cilia. In the presence of its ligand, Pdgf-AA, Mer/Erk and Akt pathways are activated.

Figure 5. Primary cilia mutations have pleiotropic effects during development

(A) Wild type primary cilia extension from a vertebrate cell during development. (B) Disrupted ciliogenesis can result in shortened and bulbous cilium (top), or complete loss of the primary cilium (bottom). (C) Primary cilia are required for proper patterning of motor neurons within the neural tube. (D) Mutations in anterograde Ift proteins (i.e. Ift88 or Kif3a) result in a dorsalization of the neural tube (left). Mutations in retrograde Ift proteins (i.e. Ift139) result in a ventralization of the neural tube (right). (E) Primary cilia are required for patterning of the limbs and digit identity. (F) Loss of primary cilia can cause polydactyly. (G) Patterning and development of the mandibular prominence of the developing craniofacial complex requires primary cilia for proper tongue and submandibular gland development. (H) Loss of primary cilia on neural crest cells in the developing mandible results in aglossia (loss of the tongue) and hypoplastic submandibular glands. (I) Patterning and development of the frontonasal prominence requires primary cilia. (J) Loss of primary cilia on neural crest cells leads to mid-facial widening, bilateral cleft palate, and a duplicated nasal septum. (K) Wild type kidney development requires functional primary cilia. (L) Mutations in primary cilia are known to cause Polycystic Kidney Disease, resulting in cysts forming within kidney.