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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Invest Dermatol. Author manuscript; available in PMC 2013 September 19.
Published in final edited form as:
PMCID: PMC3777402

The Primary Cilium: A Small Yet Mighty Organelle


Primary cilia are small, cylindrical membrane protrusions on most vertebrate cell types. Despite an unassuming appearance, this organelle has proven to be a veritable nexus of tightly regulated cell-signal reception between the epithelium and mesenchyme. In this issue, Lehman et al. describe the necessity of Ift88 and intra-flagellar transport for signal reception of the sonic hedgehog pathway in the dermal papilla of developing hair follicles.

The vertebrate hair follicle has been a model of how organs throughout the body develop, regenerate, and, upon injury, repair themselves. As new tools are employed to investigate hair development, surprising discoveries are being made with regard to the mechanisms used to precisely control tissue morphogenesis. Studies over the past two decades have established the epithelial placode, a region of crowded, multipotent epidermal keratinocytes, as the morphological onset of hair follicle (HF) development (Figure 1). Initiation of the placode requires signaling interactions between epithelial cells and adjacent dermal cells that will eventually form the specialized mesenchyme called the dermal papilla (DP). Following placode formation, the nascent HF elongates to form the hair germ and the full-length hair follicle. Elongation, as well as postnatal hair cycling, is directed by continued signaling interactions between the two tissue compartments (Fuchs et al., 2001; Millar, 2002).

Figure 1
Summary of the role of the primary cilium in epithelial–mesenchymal interactions during hair follicle morphogenesis

Molecular analyses have identified most of the key morphogens comprising the network of signals between the epithelium and the mesenchyme. These include Wnt, bone morphogenetic protein, and Notch/Delta pathways that define the early placode, in addition to sonic hedgehog (Shh) and plateletderived growth factor (PDGF) pathways that mediate the expansion of committed hair progenitor cells (Millar, 2002). In particular, the Shh ligand is expressed by the HF epithelium and received by both the epithelium and the mesenchyme, as evidenced by the expression of Shh target genes in both tissue compartments. This activity is required for elongation of the hair germ because hair follicles of Shh−/− mice do not progress past this stage. Furthermore, Shh signaling cooperates with PDGF signaling for proper DP maturation because both Shh and PDGF mutants have abnormal DP (Karlsson et al., 1999; St-Jacques et al., 1998). These studies highlight the importance of combinatorial signal transduction between tissue compartments and raise the question of how these complex interactions are regulated in the skin.

Although the identity and interactions of these morphogens are now well established, the spatial and temporal manner in which their signals are received has long been a mystery. This is particularly important given the impossibly small concentration of these morphogens and their receptors in the tissue and the powerful effects they have on the subsets of cells to which they signal. Recent genetic and cell biological studies suggest that the primary cilium (PC) is an essential point of regulation (Gao et al., 2008). The PC is a small (1–2µm) microtubule-based organelle that extends from the basal body into the extracellular space. It determines the localization of signaling molecules within its confines through intraflagellar transport (IFT) along its microtubule skeleton. In this way, the PC regulates the activity of intracellular signaling components by determining their interactions with extracellular ligands and processing machinery. In effect, this small organelle amplifies the ability of morphogens to affect receiving cells (Christensen et al., 2007).

The primary cilium is essential in the regulation of hair development.

Genetic studies indicate that the primary cilium plays a central role in vertebrate Shh signaling. The hedgehog receptor patched and the membrane-bound smoothened and the Gli transcription factors all localize to the PC. Mutations in ciliary components, which often result in Shh-relevant phenotypes, highlight the requirement of this structure for Shh signaling in developmental contexts. Mouse mutants of both anterograde IFT components, such as IFT88, and retrograde IFT components phenocopy Shh mutants of the neural tube and developing limb (Huangfu and Anderson, 2006; Michaud and Yoder, 2006). In this issue, Lehman et al. (2009) demonstrate the necessity of Ift88 in dermal cells for proper HF morphogenesis and Shh signaling in hair follicles of mice. These authors show that Ift88tm1Bky mice crossed to Prx1-cre mice, a line that specifically expresses Cre in the ventral dermis of murine skin, contain ventral dermal cells and, consequently, nascent DP, void of primary cilia. This leads to a lack of hair growth on the bellies of these mice. Histological examination of the ventral skin of such mice indicates the presence of hair follicles arrested in the hair germ stage, closely resembling the phenotype of Shh−/− mice. In addition, the nascent DP found in Prx1-cre;Ift88 mice do not express Shh target genes, leading the authors to conclude that the PC deficit in these mice leads to aberrant Shh signaling in the DP and, subsequently, stalled HF morphogenesis.

The data on IFT88 nicely complement recent work on another protein, laminin-511, which also appears to maintain PC function in the DP. Gao et al. (2008) demonstrate that laminin-511, an epithelial laminin isoform produced by HF epithelium and previously shown to be required for HF morphogenesis, also maintains the ciliary structure in dermal cells because Lamα5−/− mice lack PC. Like Prx1-cre;Ift88 mice, hair follicles of Lamα5−/− mice arrest after the formation of the short hair germ, phenocopying Shh−/− mice. Furthermore, Shh target genes are absent in the skin of Lamα5−/− mice, further implicating the PC and laminin-511 in Shh signaling (Gao et al., 2008).

A drawback of both studies is the lack of a tissue compartment–specific knockout of the PC. The Prx1-cre;Ift88 mice lack the ciliary organelle in all ventral dermal cells, not just dermal cells fated to the DP. In addition, because laminin-511 is a secreted molecule, Lamα5−/− mice may lack PC in both epidermal and dermal compartments. Given the requirement for Shh signaling in both HF epithelia and DP, disturbance of the PC specifically in each compartment should disrupt HF morphogenesis. The HF phenotype in these two models, however, could, in principle, result from disruption of the PC in multiple cell types required for HF development. Nevertheless, these results certainly designate the PC as an organelle vital for proper signal reception and tissue morphogenesis.

The involvement of the primary cilium in epithelial–mesenchymal interactions in the skin raises many questions about this sensory organelle. One issue is whether other signaling pathways depend on the PC for proper functioning in the skin. Previous data have documented the close relationship of the PC to Shh signaling, but other studies have implicated both noncanonical Wnt and PDGF signaling as well. Another issue is the role of the PC in Shh-related cancers. Basal cell carcinomas are HF-derived tumors that occur with high incidence, both spontaneously and in conjunction with basal cell nevus syndrome. This tumor is dependent on Shh signaling for its maintenance and growth and requires inappropriate Shh target gene induction for continued growth (Hutchin et al., 2005). In 1963, Wilson and McWhorter described the presence of the PC in a tumor cell of basal cell carcinoma through transmission electron microscopy (Wilson and McWhorter,1963). This suggests that the PC may play a role in tumorigenesis and that PC regulators might be potential therapeutic cancer targets.

Lehman et al. (2009), and previously Gao et al. (2008), have presented crucial investigations into the molecular requirements of normal HF morphogenesis— investigations that direct us to study similar components in tumorigenic contexts. These studies probe requirements for the formation of the PC while suggesting the existence of a host of factors that both regulate PC function and contribute to HF growth. This work suggests that we have only begun to uncover the surprising nature of this small yet mighty organelle.



The authors state no conflict of interest.


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