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Cilia functions in development


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Cilia functions in development
Iain A Drummond
Recent advances in developmental genetics and human disease gene cloning have highlighted the essential roles played by cilia in developmental cell fate decisions, left–right asymmetry, and the pathology of human congenital disorders. Hedgehog signaling in sensory cilia illustrates the importance of traf?cking receptors to the cilia membrane (Patched and Smoothened) and the concept of cilia ‘gatekeepers’ that restrict entry and egress of cilia proteins (Suppressor of fused: Gli complexes). Cilia-driven ?uid ?ow in the embryonic node highlights the role of motile cilia in both generation and detection of mechanical signals in development. In this brief review I select examples of recent studies that have clari?ed and consolidated our understanding of the role of cilia in development.
Address Nephrology Division, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, 149, 13th Street, Charlestown, MA 02129, United States Corresponding author: Drummond, Iain A (idrummond@partners.org)

simple distinction in cilia subtypes is breaking down since it is now appreciated that motile cilia also have sensory functions [4]. The wide spectrum of human pathologies, collectively termed ciliopathies, associated with mutations in genes required for cilia function includes Meckel-Gruber syndrome (MKS), nephronophthisis (NPHP), Bardet-Biedl syndrome (BBS), Joubert syndrome (JS), Senior-L?ken syndrome, Leber congenital amaurosis (LCA), polycystic kidney disease (PKD), and oral–facial–digital syndrome (OFD) [5]. Most recently, Sensenbrenner Syndrome has been added to this growing list [6–8]. The overlap in clinical features of these syndromes, including cystic kidney, laterality defects, nervous system development defects, and retinal degeneration, along with the ever expanding number of gene mutations associated with ciliopathies highlights the complexity of cilia structure and the ubiquity of cilia function [5]. I concentrate here on advances made in the past two years that help clarify how cilia serve as embryonic signaling centers and new insights into the role of cilia generated ?uid ?ow in morphogenesis.

Current Opinion in Cell Biology 2012, 24:24–30 This review comes from a themed issue on Cell structure and dynamics Edited by Jason Swedlow and Gaudenz Danuser Available online 4th January 2012 0955-0674/$ – see front matter # 2012 Elsevier Ltd. All rights reserved. DOI 10.1016/j.ceb.2011.12.007

Cilia as developmental signaling centers: recent advances in hedgehog signaling
By anchoring G-protein-coupled receptors in their membranes, primary cilia serve as a cellular ‘antenna’ for extracellular signaling molecules [9,10]. The best studied developmental signal linked to primary cilia is the Hedgehog (Hh) signaling system [11]. Genetic screens in mice lead to the unexpected ?nding that mutations in proteins required for cilia assembly, IFT proteins, disrupted neural tube patterning mediated by ventral sonic hedgehog signaling [12]. Subsequent studies implicated cilia IFT in Hedgehog signaling in endochondral bone formation [13]. Hedgehog signaling is surprisingly complex [11] and impossible to summarize in a brief review. Instead, I focus here on recent advances in our understanding of components of Hh signaling that highlight the unique functions of cilia as a ‘gated’ signaling center. In brief, resting cells express the hedgehog receptor and sterol transporter Patched on membrane at the cilia base and axoneme (Figure 1) [14]. Once bound to Hedgehog ligand, Patched is removed from the cilia membrane and inhibition of the seven-transmembrane protein Smoothened (Smo) is relieved, allowing Smo to accumulate in the cilia membrane. Cilia-localized Smo promotes accumulation of Gli transcription factor effectors of hedgehog signaling (Gli2, Gli3) and their binding factor Suppressor of fused (Sufu), speci?cally at cilia tips [15]. Gli proteins exist in full-length activator forms (GliA) and proteolytically processed repressor forms (GliR) [16]. The output of
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Introduction
Apical cilia, once ignored as vestigial, are now recognized as essential cellular organelles in the regulation of development [1]. Cilia are microtubule based structures projecting from the apical surface of nearly all cell types [2]. Motile cilia are familiar as the driving force for bronchial mucus clearance and sperm motility while primary cilia are sensory and immotile. Both motile and sensory cilia are assembled and maintained by intra?agellar transport (IFT), a microtubule motor based delivery of cilia component proteins to the growing tip (anterograde IFT) and retrieval of proteins to the cell body (retrograde IFT) [3]. Embryonic cells employ cilia to anchor membrane receptors and process incoming signals from morphogens (non-motile or sensory primary cilia) and to generate and respond to mechanical signals in the form of ?uid ?ow and shear force in con?ned spaces (mechanosensory cilia, motile cilia) [1]. Even this
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Cilia functions in development Drummond 25

Figure 1

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(b)
5 4 Hedgehog ligand

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Patched Protein Kinase A 2 3 2 1

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Smoothened Supressor of fused Gli activator

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Gli repressor

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Recent advances in cilia-mediated Hedgehog signaling. For a complete overview of Hh signaling see Ref. [11]. (a) Resting cell state with Hh signaling inhibited. The Hedgehog receptor Patched acts as a sterol efflux transporter on the cilia membrane, restricting the amount of Smoothened seven transmembrane protein present on the cilium (2). Protein kinase A activity prevents access of Sufu:Gli complexes (3) to the cilium. Cytoplasmic processing of Gli to the Gli repressor form (4) and transit to the nucleus maintains Hh target genes in a repressed state (5). (b) Activation of Hh signaling in cilia by Hh ligand binding. (1) Hedgehog ligand binds Patched (1), promoting removal from the membrane and blocking its sterol efflux function (2). Sterol bound Smoothened accumulates in the cilia membrane (3), abrogates PKA inhibition of Sufu:Gli complex entry into the cilium, allowing transport of Sufu:Gli complexes to the cilia tip (4). Cilia tip accumulation of Sufu:Gli promotes dissociation of full-length activator Gli proteins by undefined mechanisms (5), allowing Gli activator egress from the cilia (6), transit to the nucleus (7) and activation of Hh target genes.

hedgehog signaling is to shift the balance of Gli repressor to Gli activators and promote transcription of Hedgehog target genes. Cilia tip accumulation of Gli factors correlates with inhibition of Gli proteolytic processing and stabilization of activating forms of Gli proteins [15]. Thus an essential role of cilia is to regulate the ratio of GliA to GliR proteins to control transcription of hedgehog target genes. Clues as to how cilia regulate Gli protein activity have been provided by recent studies of the Gli interacting protein Suppressor of fused. Suppressor of fused (Sufu) is a Gli binding protein that inhibits Gli activity largely by sequestration in the cytoplasm [17–19]. Mutation in mammalian Sufu leads to ligand-independent activation of the Hh pathway, supporting the idea that Sufu acts as a repressor of Hh signaling [20]. The demonstration that de?ciency of Sufu can lead to full activation of Hh signaling even in the absence of cilia (Ift88 mutant cells) indicated that a primary function of cilia is to remove Sufu inhibition of Gli activity [21]. Recent biochemical studies support the idea that in resting cells, Sufu preferentially associates with full-length Gli3 and after proteolytic cleavage, GliR dissociates from the complex to represses
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Hh target genes [22]. Activation of Hh signaling promotes dissociation of full-length Gli3 activator from Sufu, allowing subsequent Gli3 phosphorylation and activation of Hh target genes [22]. Importantly, dissociation of Sufu:Gli3 complexes and Gli3A phosphorylation does not occur in cilia-de?cient (Kif3a mutant) cells stimulated with SAG, a small molecule activator of smoothened [22]. Thus a principal role of cilia in hedgehog signaling is to promote dissociation of inactive Sufu:Gli complexes, allowing the release of Gli activator proteins [23]. While many additional aspects of hedgehog signaling remain to be worked out, an intriguing question is how transit of Sufu:Gli complexes to cilia tips promotes Sufu:Gli dissociation. The cilia tip is the active zone of cilia growth; here, anterograde IFT raft cargo is released and re-assembled with other axonemal proteins to extend the cilium [24]; retrograde IFT then recycles transport proteins to the cilia base [25]. Cilia de?cient in retrograde IFT accumulate proteins at the cilia tip resulting in bulbous tip membrane protrusions [26]. It will be interesting to see whether cilia tip associated mechanisms of Sufu:Gli dissociation have co-opted cellular machinery originally evolved for dissociating IFT raft cargo. It will
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26 Cell structure and dynamics

also be important to resolve the somewhat puzzling role of retrograde IFT in Gli transport and processing since mutation in the retrograde IFTA motor Dync2h1 inhibits Hh signaling [27,28] while mutation in other retrograde IFTA proteins activates Hh signaling [26,29]. Clari?cation of these results is likely to come from modeling cilia association of Hh signaling proteins as the outcome of shifting the equilibrium toward cilia retention of proteins that are constantly shuttled in and out of the cilium [28], as opposed to a strictly gated process. For instance, the concept of cilia traf?cking equilibria has recently been put forward to account for ?ndings that hedgehog signaling de?cits caused by the loss of the retrograde IFT A motor Dync2h1 can be compensated by reduction in the levels of anterograde IFT B proteins [30].

conserved protein responsible for maintaining distinct membrane domains in budding yeast, is also expressed in the ciliary necklace region and functions there as a barrier to membrane protein diffusion [40]. These observations indicate that multiple cilia membrane-associated barriers regulate traf?cking of speci?c proteins to and from the cilium. In addition, speci?c apical membrane retention signals can restrict diffusion of proteins into the cilium [41]. Elucidation of the molecular nature of the transition zone and protein sorting signals should yield new insights into how cilia membrane composition is regulated and ultimately how cilia signaling is controlled. Cilia membrane protein transport is mediated by cilia targeted coatamer-like proteins (the ‘BBSome’ [42]) and by the activity of multiple small GTPases including rab8, rab11, and rab23 [43,44]. The temporal sequence of rab8, rabin8, a rab8 guanine nucleotide exchange factor, and rab11 activities in ciliogenesis has recently been elegantly demonstrated by live cell imaging [45]. Further studies of other cilia-associated small GTPases including arf4, arl13b, arl2, arl3, arl6, rabl4/IFT27, and rabl5/IFT25 [46] are likely to identify molecular switches that regulate cilia gatekeeper functions, cilia membrane composition, and cilia structure [47,48].

Gatekeepers of protein traf?cking in the cilium
Control of both initiation of Hedgehog signaling and subsequent processing of Gli proteins is critically dependent on access of signaling receptors (Smo) and downstream effectors (Gli) to the ciliary compartment. For instance, Protein kinase A, a known inhibitor of hedgehog signaling, acts by preventing access of Sufu:Gli complexes to the cilia, thus preventing Sufu:Gli dissociation and Gli activation [23,31,32]. Access to the cilium is likely to be a general principle in cilia function affecting many cell-type-speci?c cilia signaling systems. The cilia transition zone, a short segment of the cilium just above the basal body, has recently been implicated as an essential ‘gatekeeper’ that limits or controls diffusion of membrane proteins in and out of the cilium (Figure 2) [33]. This proposed function of the transition zone is correlated with the presence of ‘Y-links’, structures that link cilia microtubule doublets to the cilia membrane in position to restrict membrane protein diffusion or regulate IFT [33]. The signi?cance of the transition zone is highlighted by recent reports that a complex of proteins encoded by genes found to be mutated in syndromic ciliopathies (MKS/NPHP) function as a multiprotein complex in the cilia transition zone [34] and act as a barrier to membrane protein diffusion [35,36]. Whether MKS/NPHP proteins are part of the Y-link structure or whether they perform a regulatory function in cilia traf?cking remains to be determined. Another barrier or ‘gate’ controlling access to cilia is the so-called ‘ciliary necklace’, a ring of intramembrane proteins at the junction of the apical plasma membrane and the cilia base adjacent to the transition zone (Figure 2). Recent reports establish an unexpected function for components of the nuclear pore complex in transit of proteins past the ciliary necklace [37,38]. The nuclear pore complex regulates traf?c in and out of the nucleus [39]. Importin b and the small GTPase ran are key elements of this transport system that have now been shown to also function in regulating protein transit to the cilium via the ciliary necklace [37,38]. Septin 2, a highly
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Cilia, ?uid ?ow, and development
Another major function of cilia in development is to generate ?uid movement in con?ned embryonic spaces and to sense and interpret ?uid shear force (mechanotransduction) as a developmental signal. The best studied example of this occurs in the embryonic node, or Kupffer’s vesicle (KV) in ?sh, where leftward ?uid ?ow is harnessed as a developmental cue for breaking left–right symmetry. Seminal ?ndings of left–right asymmetry disorders in human patients with immotile cilia syndromes [49] ultimately lead to the discovery of motile cilia and ?uid ?ow in the mouse node [50], a transient embryonic midline structure. In the node, anterior–posterior polarity is transformed into left–right polarity by the action of planar polarity signaling on cilia basal body position and orientation (reviewed in [51]). Tipping the basal body to the posterior results in an asymmetric cilia beat stroke and a strong leftward ?ow and a weaker rightward return ?ow [52]. Asymmetric left-sided expression of Nodal is observed after the initiation of ?ow and arti?cial reversal of ?ow is suf?cient to reverse situs [53]. So how might ?uid ?ow be transduced into a morphogenetic signal? One view is the ?ow delivers lipid-encapsulated morphogens preferentially to the left side of the embryo [54]. However for this to work, released morphogens would have to be avidly removed from circulation on the left side since return rightward ?ow would randomize their distribution in the node. As an alternative, a compelling case for leftsided mechanotransduction by cilia can be made. This idea posits that both motile and sensory cilia exist in the node, with sensory cilia positioned at the edges of the
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Cilia functions in development Drummond 27

Figure 2

36

34

Cep290 Y-Links Ciliary necklace 40 Septin

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Inversin zone

Nphp9 Nphp2 Nphp3 Nphp8 Nphp1 Nphp4

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Transition zone Basal Body

Nphp1 Nphp4 Mks5 Mks6 Mks3 Mks1 Mksr1 Mksr2

Tctn1 Mks1 Cc2d2a B9d1 Tctn2 Tctn3
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Importin β ran

Nphp5 Nphp6 Nphp2

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The ciliary gate. The ciliary necklace and transition zone lie just above the basal body and play important roles in limiting diffusion of cilia membrane proteins and regulating cilia protein traffic. Septin expression in the ciliary necklace demarcates the apical cell membrane (blue) from the cilia membrane (red). Other protein complexes contribute to Y-link structures (Cep290) and to regulated trafficking or retention of cilia proteins (Importin b/ran and complexes of NPHP/MKS proteins). Boxed proteins represent biochemically defined complexes identified in the noted references.

node to transduce ?ow into an increase in intracellular calcium, ultimately signaling left-sided Nodal expression [55]. This model is supported by ?ndings that calcium is elevated on the left side of the node [55] and knockdown or mutations in the cilia-associated calcium channel Polycystin2 (PKD2) result in randomized L/R asymmetry [56,57]. PKD2 is one of two genes mutated in Autosomal dominant polycystic kidney disease [58]. The other, PKD1, interacts with PKD2 to form active ion channels [59]. A somewhat puzzling ?nding was that PKD1 is not expressed in the node; so how do PKD2 proteins form an active channel? The answer recently reported by two groups is that a PKD1 ortholog, PKD1L1, is expressed in its place in the node and mutations in PKD1L1 lead to left–right asymmetry defects [60,61]. A surprising outcome of these studies is that PKD1L1 is expressed, at least in Medaka ?sh, on all KV cilia, including motile cilia [61]. Can cilia be both motile and sensory? Precedent for this is seen in human airway cilia where bitter taste receptors are present on motile cilia and can signal changes in cilia beat rate [62]. Lung and oviduct motile cilia also respond to mechanical resistance and the viscosity of the medium by altering their beat rate, a homeostatic response that ensures continued medium propulsion (reviewed in [4]). In the node, motile cilia may encounter resistance to beating in areas of increased local ?ow and relay this mechanical signal by elevating cytoplasmic calcium. One further level of complexity in cilia mechanotransduction is that the calcium wave induced in ciliated epithelial cells by ?uid ?ow is not directly propagated by cilium bending but rather by ATP
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secretion and stimulation of purinergic receptors on neighboring cells [63–65]. Since purinergic receptors are ubiquitous in embryos and signal via calcium release [66], it will be interesting to see whether they play a role in propagating node calcium signaling and establishment of L/R asymmetry. In addition to signaling in the embryonic node, ciliadriven ?uid ?ow impacts morphogenesis of the larval zebra?sh kidney as well as development of the mammalian brain. In the zebra?sh pronephros, motile cilia-driven ?uid ?ow signals collective migration of epithelial tubule cells, resulting in convolution of the nephron and functional association with the vasculature [67]. In the brain, cerebrospinal ?uid (CSF) is circulated by motile cilia and cilia defects cause ?uid back pressure leading to hydrocephalus or swelling of the brain ventricles [68]. In addition, directional migration of neuroblasts from the subventricular zone to the olfactory bulb occurs in response to CSF ?ow and establishment of a concentration gradient of guidance molecules [69]. Also, in the developing central nervous system, spontaneous rhythmic ?ring of neurons is required to establish proper neuronal connectivity. A recent report presents provocative ?ndings that rhythmic neuronal activity is dependent on ?uid ?ow, in this case most likely providing a ?uid shear mechanical signal that stimulates neural activity [70].

Conclusions
Cilia serve multiple roles in development and function in highly context dependent ways. Sensory cilia display a
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28 Cell structure and dynamics

unique spectrum of receptors depending on the cell type and can impact development in diverse ways. Motile cilia exert long range, non-cell autonomous effects via generating ?uid ?ow, and thereby guiding tissue morphogenesis under the control of mechanical signals. That cilia can be both motile and sensory offers new possibilities for interpreting cilia function. Now that proteomic analysis of cilia has identi?ed over 1,000 cilia-associated proteins, we can expect many new insights on cilia gene function in the next few years. The ?eld has moved beyond simple association of cilia gene mutations with pathology; our current and future goals should be to determine how different complexes of proteins function together to carry out speci?c cilia functions or build cilia substructures. To this end, biochemical protein interaction studies, analysis of compound genetic mutants, and high resolution electron microscopic structural analysis will all play essential roles in determining how cilia work. Finally, cilia are not static structures; they adapt to signals in their environment and alter their structure or activity in response [71,72]. Future studies promise to integrate subcellular structure of the cilium with cell physiology, developmental patterning, and morphogenesis while revealing new aspects of the dynamic nature of these organelles.

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Acknowledgements
The author gratefully acknowledges the contributions of Narendra Pathak and Danica Rili for editorial suggestions. This work was funded by the National Institututes of Health grant number DK053093 to IAD.

References and recommended reading
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Cilia functions in development Drummond 29

Shah JV et al.: THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intra?agellar transport in cilia. Nat Genet 2008, 40:403-410. 27. Huangfu D, Anderson KV: Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A 2005, 102:11325-11330. 28. Kim J, Kato M, Beachy PA: Gli2 traf?cking links Hedgehogdependent activation of Smoothened in the primary cilium to transcriptional activation in the nucleus. Proc Natl Acad Sci U S A 2009, 106:21666-21671. 29. Qin J, Lin Y, Norman RX, Ko HW, Eggenschwiler JT: Intra?agellar transport protein 122 antagonizes Sonic Hedgehog signaling and controls ciliary localization of pathway components. Proc Natl Acad Sci U S A 2011, 108:1456-1461. 30. Ocbina PJ, Eggenschwiler JT, Moskowitz I, Anderson KV: Complex interactions between genes controlling traf?cking in primary cilia. Nat Genet 2011, 43:547-553. 31. Tuson M, He M, Anderson KV: Protein kinase A acts at the basal body of the primary cilium to prevent Gli2 activation and ventralization of the mouse neural tube. Development 2011, 138:4921-4930. 32. Zeng H, Jia J, Liu A: Coordinated translocation of mammalian Gli proteins and suppressor of fused to the primary cilium. PLoS ONE 2010, 5:e15900. 33. Craige B, Tsao CC, Diener DR, Hou Y, Lechtreck KF,  Rosenbaum JL, Witman GB: CEP290 tethers ?agellar transition zone microtubules to the membrane and regulates ?agellar protein content. J Cell Biol 2010, 190:927-940. Using a Chlamydomonas mutant in the ciliopathy gene Cep290, the authors show that cilia membrane protein is randomized, pointing to a central role for NPHP/MKS/BBS proteins in regulating cilia membrane protein traf?cking. 34. Sang L, Miller JJ, Corbit KC, Giles RH, Brauer MJ, Otto EA,  Baye LM, Wen X, Scales SJ, Kwong M et al.: Mapping the NPHP– JBTS–MKS protein network reveals ciliopathy disease genes and pathways. Cell 2011, 145:513-528. Using comprehensive biochemical and genetic approaches, this work demonstrated that NPHP–JBTS–MKS proteins can be be clustered into three biochemically and functionally distinct modules localized to cilia substructures. 35. Williams CL, Li C, Kida K, Inglis PN, Mohan S, Semenec L,  Bialas NJ, Stupay RM, Chen N, Blacque OE et al.: MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J Cell Biol 2011, 192:1023-1041. An indepth study of C. elegans NPHP/MKS proteins revealed a consistent transition zone localization of these proteins, biochemical interactions between different complex members, and genetic interactions that de?ned their role in regulating cilia structure. 36. Garcia-Gonzalo FR, Corbit KC, Sirerol-Piquer MS, Ramaswami G,  Otto EA, Noriega TR, Seol AD, Robinson JF, Bennett CL, Josifova DJ et al.: A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nat Genet 2011, 43:776-784. This paper and [34,35] de?ned the function of syndromic ciliopathy proteins as regulators of cilia transition zone function. 37. Dishinger JF, Kee HL, Jenkins PM, Fan S, Hurd TW, Hammond JW,  Truong YN, Margolis B, Martens JR, Verhey KJ: Ciliary entry of the kinesin-2 motor KIF17 is regulated by importin-beta2 and RanGTP. Nat Cell Biol 2010, 12:703-710. An unexpected and novel relationship is de?ned between mechanisms of nuclear protein traf?cking and cilia protein traf?cking. 38. Hurd TW, Fan S, Margolis BL: Localization of retinitis pigmentosa 2 to cilia is regulated by Importin beta2. J Cell Sci 2011, 124:718-726. 39. Stewart M: Molecular mechanism of the nuclear protein import cycle. Nat Rev Mol Cell Biol 2007, 8:195-208. 40. Hu Q, Milenkovic L, Jin H, Scott MP, Nachury MV, Spiliotis ET, Nelson WJ: A septin diffusion barrier at the base of the primary cilium maintains ciliary membrane protein distribution. Science 2010, 329:436-439. www.sciencedirect.com

41. Francis SS, Sfakianos J, Lo B, Mellman I: A hierarchy of signals regulates entry of membrane proteins into the ciliary membrane domain in epithelial cells. J Cell Biol 2011, 193:219-233. 42. Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller RH, Bazan JF, Shef?eld VC et al.: A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 2007, 129:1201-1213. 43. Knodler A, Feng S, Zhang J, Zhang X, Das A, Peranen J, Guo W: Coordination of Rab8 and Rab11 in primary ciliogenesis. Proc Natl Acad Sci U S A 2010, 107:6346-6351. 44. Eggenschwiler JT, Bulgakov OV, Qin J, Li T, Anderson KV: Mouse Rab23 regulates hedgehog signaling from smoothened to Gli proteins. Dev Biol 2006, 290:1-12. 45. Westlake CJ, Baye LM, Nachury MV, Wright KJ, Ervin KE, Phu L, Chalouni C, Beck JS, Kirkpatrick DS, Slusarski DC et al.: Primary cilia membrane assembly is initiated by Rab11 and transport protein particle II (TRAPPII) complex-dependent traf?cking of Rabin8 to the centrosome. Proc Natl Acad Sci U S A 2011, 108:2759-2764. 46. Li Y, Hu J: Small GTPases and cilia. Protein Cell 2011, 2:13-25. 47. Li Y, Wei Q, Zhang Y, Ling K, Hu J: The small GTPases ARL-13 and ARL-3 coordinate intra?agellar transport and ciliogenesis. J Cell Biol 2010, 189:1039-1051. 48. Mazelova J, Astuto-Gribble L, Inoue H, Tam BM, Schonteich E, Prekeris R, Moritz OL, Randazzo PA, Deretic D: Ciliary targeting motif VxPx directs assembly of a traf?cking module through Arf4. EMBO J 2009, 28:183-192. 49. Afzelius BA: Genetical and ultrastructural aspects of the immotile-cilia syndrome. Am J Hum Genet 1981, 33:852-864. 50. Nonaka S, Tanaka Y, Okada Y, Takeda S, Harada A, Kanai Y, Kido M, Hirokawa N: Randomization of left–right asymmetry due to loss of nodal cilia generating leftward ?ow of extraembryonic ?uid in mice lacking KIF3B motor protein. Cell 1998, 95:829-837. 51. Hashimoto M, Hamada H: Translation of anterior–posterior polarity into left–right polarity in the mouse embryo. Curr Opin Genet Dev 2010, 20:433-437. 52. Nonaka S, Yoshiba S, Watanabe D, Ikeuchi S, Goto T, Marshall WF, Hamada H: De novo formation of left–right asymmetry by posterior tilt of nodal cilia. PLoS Biol 2005, 3:e268. 53. Nonaka S, Shiratori H, Saijoh Y, Hamada H: Determination of left–right patterning of the mouse embryo by arti?cial nodal ?ow. Nature 2002, 418:96-99. 54. Tanaka Y, Okada Y, Hirokawa N: FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward nodal ?ow is critical for left–right determination. Nature 2005, 435:172-177. 55. McGrath J, Somlo S, Makova S, Tian X, Brueckner M: Two populations of node monocilia initiate left–right asymmetry in the mouse. Cell 2003, 114:61-73. 56. Pennekamp P, Karcher C, Fischer A, Schweickert A, Skryabin B, Horst J, Blum M, Dworniczak B: The ion channel polycystin-2 is required for left–right axis determination in mice. Curr Biol 2002, 12:938-943. 57. Obara T, Mangos S, Liu Y, Zhao J, Wiessner S, Kramer-Zucker AG, Olale F, Schier AF, Drummond IA: Polycystin-2 immunolocalization and function in zebra?sh. J Am Soc Nephrol 2006, 17:2706-2718. 58. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A et al.: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996, 272:1339-1342. 59. Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG: PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet 1997, 16:179-183. 60. Field S, Riley KL, Grimes DT, Hilton H, Simon M, Powles-Glover N,  Siggers P, Bogani D, Green?eld A, Norris DP: Pkd1l1 establishes Current Opinion in Cell Biology 2012, 24:24–30

30 Cell structure and dynamics

left–right asymmetry and physically interacts with Pkd2. Development 2011, 138:1131-1142. Using a genetic approach, this work resolves a mystery about the function of polycystin ion channel complexes in mechanotransduction of nodal ?uid ?ow by identifying PKD1L1 as a key element in generating left–right asymmetry. 61. Kamura K, Kobayashi D, Uehara Y, Koshida S, Iijima N, Kudo A,  Yokoyama T, Takeda H: Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish the left–right axis. Development 2011, 138:1121-1129. Published along with Ref. [60], this work arrives at similar ?ndings from a completely different angle: positional cloning a Medaka ?sh mutant. The authors also present the provocative ?nding that the proposed Pkd2:PKD1L1 sensory ion channel is present exclusively on motile cilia, challenging the idea that the only non-motile ciila can be sensory and offering chemosensory or mechanosensory roles for motile cilia. 62. Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ: Motile cilia of human airway epithelia are chemosensory. Science 2009, 325:1131-1134. 63. Hovater MB, Olteanu D, Hanson EL, Cheng N-L, Siroky B, Fintha A, Komlosi P, Liu W, Satlin LM, Bell PD et al.: Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and ?ow-induced calcium signals. Puriner Signal 2007, 4:155-170. 64. Xu C, Shmukler BE, Nishimura K, Kaczmarek E, Rossetti S, Harris PC, Wandinger-Ness A, Bacallao RL, Alper SL: Attenuated, ?ow-induced ATP release contributes to absence of ?owsensitive, purinergic Cai2+ signaling in human ADPKD cyst epithelial cells. Am J Physiol Renal Physiol 2009, 296:F1464-F1476. 65. Praetorius HA, Leipziger J: Released nucleotides amplify the cilium-dependent, ?ow-induced [Ca2+]i response in MDCK cells. Acta Physiol 2009, 197:241-251.

66. Burnstock G, Ulrich H: Purinergic signaling in embryonic and stem cell development. Cell Mol Life Sci 2011, 68:1369-1394. 67. Vasilyev A, Liu Y, Mudumana S, Mangos S, Lam PY, Majumdar A, Zhao J, Poon KL, Kondrychyn I, Korzh V et al.: Collective cell migration drives morphogenesis of the kidney nephron. PLoS Biol 2009, 7:e9. 68. Ibanez-Tallon I, Pagenstecher A, Fliegauf M, Olbrich H, Kispert A, Ketelsen UP, North A, Heintz N, Omran H: Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal ?ow and reveals a novel mechanism for hydrocephalus formation. Hum Mol Genet 2004, 13:2133-2141. 69. Sawamoto K, Wichterle H, Gonzalez-Perez O, Chol?n JA, Yamada M, Spassky N, Murcia NS, Garcia-Verdugo JM, Marin O, Rubenstein JL et al.: New neurons follow the ?ow of cerebrospinal ?uid in the adult brain. Science 2006, 311:629-632. 70. Yvert B, Mazzocco C, Joucla S, Langla A, Meyrand P: Arti?cial CSF motion ensures rhythmic activity in the developing CNS ex vivo: a mechanical source of rhythmogenesis? J Neurosci 2011, 31:8832-8840. 71. Hellman NE, Liu Y, Merkel E, Austin C, Le Corre S, Beier DR, Sun Z, Sharma N, Yoder BK, Drummond IA: The zebra?sh foxj1a  transcription factor regulates cilia function in response to injury and epithelial stretch. Proc Natl Acad Sci U S A 2010, 107:18499-18504. This work demonstrates that signals in injured cells rapidly stimulate a transcriptional cascade initiated by foxj1 that controls motile ciliogenesis, highlighting a novel role for cilia dynamics in injury and regeneration. 72. Mukhopadhyay S, Lu Y, Shaham S, Sengupta P: Sensory signaling-dependent remodeling of olfactory cilia architecture in C. elegans. Dev Cell 2008, 14:762-774.

Current Opinion in Cell Biology 2012, 24:24–30

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