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Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition

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Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Open Sesame: How Transition Fibers and the Transition Zone Control Ciliary Composition Francesc R. Garcia-Gonzalo1 and Jeremy F. Reiter2 1Departamento de Bioquı´mica, Facultad de Medicina, and Instituto de Investigaciones Biome´dicas Alberto Sols UAM-CSIC, Universidad Auto´noma de Madrid, 28029 Madrid, Spain 2Department of Biochemistry and Biophysics, and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94158 Correspondence: [email protected]; [email protected] Cilia are plasma membrane protrusions that act as cellular propellers or antennae. Toperform these functions, cilia must maintain a composition distinct from those of the contiguous cytosol and plasma membrane. The specialized composition of the cilium depends on the ciliary gate, the region at the ciliary base separating the cilium from the rest of the cell. The ciliary gate’s main structural features are electron dense struts connecting microtubules to the adjacent membrane. These structures include the transition fibers, which connect the distal basal body to the base of the ciliary membrane, and the Y-links,which connect the proximal axoneme and ciliary membrane within the transition zone. Both transition fibers and Y-links form early during ciliogenesis and play key roles in ciliary assembly and trafficking. Accordingly, many human ciliopathies are caused by mutations that perturb ciliary gate function. ilia are born from the docking of a mother to form. This proximal region of the cilium, Ccentriole to a membrane. The interaction known as the transition zone (TZ), begins at of centriole and membrane depends on the the distal end of the basal body and is de- centriolar distal appendages, whose tips anchor fined by the presence of Y-links, bifid fibers to the membrane. In the context of ciliogene- connecting each TZ microtubule doublet to sis, these membrane-anchored distal append- the adjacent membrane (Fig. 1). Perhaps be- ages are often referred to as transition fibers cause of their tethering to microtubules, ciliary (TFs) (Fig. 1). After this early ciliogenic step, gate membranes are particularly resistant to the nine concentric microtubule triplets in the detergent extraction and harbor specialized centriole, now referred to as the basal body, act proteinaceous structures like the ciliary neck- as templates onto which the nine axonemal lace (Fig. 1) (Gilula and Satir 1972; Horst et al. microtubule doublets are constructed. Because 1987). axoneme growth and disassembly occur only at The ciliary gate sits at the juncture between its distal tip, the basal-most axoneme is the first the basal body and axoneme, between the plas- Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2016 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028134 1 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press F.R. Garcia-Gonzalo and J.F. Reiter A B Transition fibers Transition zone tf Ciliary membrane Ciliary lumen Transverse Axoneme Y-links Transition zone Ciliary Longitudinal * necklace C Ciliary gate Transition fibers Plasma membrane Basal body Figure 1. Ultrastructure of the ciliary gate. (A) Schematic showing the different parts of a cilium, with emphasis on the ciliary gate comprised by the transition fibers and the transition zone. (From Reiter et al. 2012; adapted, with permission, from the authors.) (B) Electron microscopic images of the transition fibers and transition zone. Left panels show transition fibers in transverse. (Top, from O’Toole et al. 2003; adapted, with permission, from the American Society for Cell Biology # 2003; and longitudinal [bottom] views from Tateishi et al. 2013; reprinted under a Creative Commons License [Attribution–Noncommercial–Share Alike 3.0 Unported li- cense, as described at creativecommons.org/licenses/by-nc-sa/3.0].) Arrows point to transition fibers (tf ). Right panels show transverse and longitudinal views of transition zones from rat photoreceptor connecting cilia (From data in Horst et al. 1987; adapted, with permission, from the authors.) Arrows point to Y-links. Asterisk marks the distal end of the transition zone (TZ). (C) Freeze-fracture etching of the ciliary necklace of a rat tracheal cilium. (Image adapted from data in Gilula and Satir 1972.) Arrowheads point to beads in the ciliary necklace. ma membrane and ciliary membrane, and be- gate region. We conclude by identifying out- tween the cytosol and ciliary lumen (Fig. 1), and standing questions in the field. thus is in a position to regulate proteins enter- ing and exiting the cilium. A decade ago, little was known about this region other than its ul- TRANSITION FIBERS trastructure. The last 10 years, however, have Transition Fiber Architecture changed that: proteomes and interactomes of the ciliary gate and several of its components Basal bodies start their lives as mother centri- have been generated, superresolution microsco- oles, distinguished from daughter centrioles by py has helped localize several gate components, the distal appendages through which they dock loss of function genetic studies have elucidated to the vesicles that are eventually remodeled functional modules, and many ciliary gate genes into the ciliary membrane (Sorokin 1962; Lu have been linked to specific human ciliopathies. et al. 2015). When associated with the ciliary We are now at the point where an integrated membrane or its precursors, centriolar distal understanding of how the ciliary gate controls appendages are referred to as transition fibers ciliary composition can be anticipated. Below, (TFs) or alar sheets. Although the former term we review the architecture, composition, func- has gained general acceptance, the latter is evoc- tion, and disease involvement of each ciliary ative of their shape: wing-like trapezoidal sheets 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028134 Downloaded from http://cshperspectives.cshlp.org/ on September 29, 2021 - Published by Cold Spring Harbor Laboratory Press Controlling Ciliary Composition (Anderson 1972). There are nine TFs, each of ranged to give rise to these structures remains to which emerges from the distal portion of the C- be determined. tubule of the basal body and ends at an electron dense knob at the most proximal ciliary mem- Transition Fiber Functions brane (Fig. 1) (Gibbons and Grimstone 1960; Ringo 1967). Cross sections suggest that there is An early step in ciliogenesis is the recruitment of 60 nm between adjacent TFs, enough so that a small vesicles to the distal appendages of a ribosome, but not a vesicle, might pass between mother centriole, the distal appendage vesicles them (Nachury et al. 2010). Because the basal (DAVs). The DAVs fuse to form a larger ciliary body lumen is obstructed by centrin-2-con- vesicle that caps the distal centriole in a process taining electron dense structures (Fisch and that depends on EHD1 and EHD3 (Lu et al. Dupuis-Williams 2011), these spaces between 2015). Expansion of this ciliary vesicle gives TFs are likely to be the main passageways rise to the ciliary membrane, which is assem- for macromolecules entering and exiting the bled in parallel with the axoneme. Axoneme cilium. outgrowth is associated with removal from the The TF is comprised of at least five proteins distal mother centriole of CP110, a protein with (Graser et al. 2007; Sillibourne et al. 2011; Joo both positive and negative roles in early cilio- et al. 2013; Tanos et al. 2013). Hierarchical lo- genesis (Spektor et al. 2007; Tsang et al. 2008; calization analysis shows that Cep83 (also called Kobayashi et al. 2011; Yadav et al. 2016). Axo- Ccdc41) is required for the localization of neme formation also involves the construction Cep89 (also called Ccdc123 or Cep123) and of the TZ and recruitment of intraflagellar Sclt1, and the latter is required for localizing transport (IFT) particles, the microtubule mo- Fbf1 and Cep164 (Tanos et al. 2013). Many of tor-driven complexes that mediate ciliary trans- these core TF components are required for basal port and assembly (Lu et al. 2015). body docking to a membrane and ciliogenesis Disrupting distal appendage formation or (Schmidt et al. 2012; Tanos et al. 2013; Joo et al. function (e.g., interfering with Ofd1, C2cd3, 2013; Tateishi et al. 2013; Burke et al. 2014; Ye Odf2, Cep164, or Cep83) blocks ciliogenesis et al. 2014). Another protein, Chibby (Cby1), is and, in all cases where it has been examined, recruited to TFs by Cep164 and extends toward prevents DAV formation (Singla et al. 2010; the proximal TZ, but is dispensable for at least Schmidt et al. 2012; Joo et al. 2013; Tanos et al. some forms of ciliogenesis (Voronina et al. 2013; Tateishi et al. 2013; Burke et al. 2014; 2009; Burke et al. 2014; Lee et al. 2014). In Thauvin-Robinet et al. 2014; Ye et al. 2014). turn, TF localization of all the above proteins Moreover, TFs are essential to remove CP110 requires components of the distal centriole, in- from the distal centriole and recruit TZ and cluding Ofd1 and C2cd3, two proteins that, de- IFT proteins to the ciliary base (Deane et al. spite their shared role in building the distal ap- 2001; Schmidt et al. 2012; Joo et al. 2013; Tanos pendages, exert opposite effects on centriole et al. 2013; Cˇ aja´nek and Nigg 2014; Ye et al. length (Singla et al. 2010; Thauvin-Robinet 2014). et al. 2014; Ye et al. 2014), and Odf2 (Cenexin), Cep164 is a key TF component that pro- a Cby1 interactor required for the formation of motes ciliogenesis through several mechanisms. both distal and subdistal centriolar appendages First, facilitated by Cby1, Cep164 interacts with (Ishikawa et al.
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