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Evolution of Cilia

David R. Mitchell

Department of Cell and Developmental Biology, SUNY Upstate Medical University, Syracuse, New York13210 Correspondence: [email protected]

Anton van Leeuwenhoek’s startling microscopic observations in the 1600s first stimulated fascination with the way that cells use cilia to generate currents and to swim in a fluid environment. Research in recent decades has yielded deep knowledge about the mechanical and biochemical nature of these organelles but only opened a greater fascination about how such beautifully intricate and multifunctional structures arose during evolution. Answers to this evolutionary puzzle are not only sought to satisfy basic curiosity, but also, as stated so eloquently by Dobzhansky (Am Zool 4: 443 [1964]), because “nothing in biology makes sense except in the light of evolution.” Here I attempt to summarize current knowl- edge of what ciliary organelles of the last eukaryotic common ancestor (LECA) were like, explore the ways in which cilia have evolved since that time, and speculate on the selective processes that might have generated these organelles during early eukaryotic evolution.

everal excellent papers have appeared in the and motility regulation, and these organisms Srecent past that follow evolution of structures include representatives of phylogenetically dis- or complexes essential to ciliary function, in- tant groups (green algae, ciliates, excavates, met- cluding reviews on basal bodies and centrioles azoa). Together with genomic data, these func- (Hodges et al. 2010; Ross and Normark 2015) tional and structural studies provide a basis and centrosomes (Azimzadeh 2014), trafficking for understanding common features of cilia and signaling modules (Johnson and Leroux that would have been present in the last com- 2010; Lim et al. 2011; Sung and Leroux 2013; mon ancestor as well as changes that may have Malicki and Avidor-Reiss 2014), tubulins (Fin- occurred since that time. These aspects of ciliary deisen et al. 2014), transition-zone complexes evolution can, therefore, be presented with only (Barker et al. 2014), and cilia themselves a modest level of speculation, and speculative (Satir et al. 2008; Carvalho-Santos et al. 2011). aspects are likely to be short-lived as additional Rather than attempting to cover all of the same data is collected. ground in a single review, I will refer the reader Knowing how cilia evolved in the first place, to other sources where appropriate and in- during those dark ages of eukaryotic evolu- stead try to look at the bigger pictures that are tion after formation of true eukaryotes but be- emerging from these details. Importantly, many fore diversification into currently recognized model organisms have contributed to studies supergroups, provides greater challenges. Evo- of cilia-related processes such as intraflagellar lutionary change includes continuous (as well transport (IFT) trafficking, centriole assembly, as sudden and catastrophic) extinctions, which

Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a028290 Cite this article as Cold Spring Harb Perspect Biol 2017;9:a028290

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D.R. Mitchell

for the most part leave no trace in the genomic distant branches of the tree of life. Such is cer- record of extant organisms. For larger, multicel- tainly the case with prokaryotes, whose division lular species and for those with hard shells or into eubacteria and archaea was largely depen- tests, fossils may provide some clues to morpho- dent on sequence comparisons, not shape, but logic features of extinct clades. For single-celled similar discoveries have been made among eu- eukaryotes that existed before the last eukaryot- karyotes such as oomycetes, which look like ic common ancestor (LECA), and especially for fungi but clearly belong in stramenopiles, and evidence of their motile mechanisms, fossils more recently with apusozoa, which resemble provide little information. We are, therefore, re- amoebae but are more closely related to us duced to analysis of genomic changes between (Paps et al. 2013; Cavalier-Smith et al. 2014). the closest living prokaryotic relatives of eu- The tree in Figure 1 summarizes many recent karyotes, as a proxy for the first eukaryotic an- studies on the relationships among extant eu- cestor, and the inferred common set of genes of karyotes. Disagreement remains on some of the LECA, to learn how cilia evolved. Missing the deep connections in this tree, in part because from this equation are data on other evolution- we still lack genomic sequences of some well- ary paths leading to development of motile or- known eukaryotes and in part because some ganelles (perhaps resembling cilia or perhaps genomes appear to be evolving so fast that rela- not) that might have flourished for some time tionships are difficult to establish. Of course but that became extinct and left no trace in the many other species remain to be discovered current record. and some of these could reveal previously un- appreciated relationships, but such trees remain useful because structures, mechanisms, and in- THE CILIATED ORGANELLE OF THE LECA dividual proteins that are found in multiple When it comes to single-celled organisms, there branches must have existed in the last common is only so much to be learned from morpho- ancestor of those divergent species, regardless of logical features. Many species that were once their true phylogenetic relationships. thought to be closely related, based on outward Comparison of many recently generated appearance, have turned out to belong to quite trees of eukaryotic phylogeny leads to two strik-

96-nm repeat A Bikonts B Dimeric ODAs Unikonts Excavata SAR Higher plants MIA complex Amoebozoa Green algae Dimeric IDA Metazoa Red algae Fungi Glaucophytes Base Tip Apusozoa Monomeric IDAs Spokes S1 S2 S3 Plastid DRC/nexin LECA Central pair complex

Figure 1. (A) Diagram of major eukaryotic clades diverging from a last eukaryotic common ancestor (LECA), with the root placed between unikont and bikont superclades. Branches are color-coded according to differences in orientation of ciliary central-pair microtubules, which appear perpendicular to the bend plane and fixed in unikonts (blue), perpendicular to the bend plane but floating in excavates (orange), and twisted (helical) and rotating in other bikonts (green). The LECA is cartooned as a single cell with a nucleus, a mitochondrion, and two flagella: an anterior motile flagellum and a posterior gliding flagellum. The dashed arrow indicates the first acquisition of a plastid through endosymbiosis of a cyanobacterium. (B) Diagrams of ciliary axonemal struc- tures that were present in the LECA. (Left) Cross-sectional view from inside the cell. (Right) Longitudinal view of one 96-nm repeat along an outer doublet. MIA, Modifier of inner arms; ODA, outer dynein arm; IDA, inner dynein arm; DRC, dynein regulatory complex.

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Evolution of Cilia

ing conclusions. First, it is very difficult to sort singlet microtubules, assembled on basal bodies out the branch order at the base of the tree, built from nine triplet microtubules. Motility because all the major branches of eukaryotes generated by both outer and inner rows of dy- seem to have diverged from a common ancestor nein arms was regulated by interactions between within a short time (Fig. 1A). As with evolution radial spokes and a central-pair complex, and anywhere, anytime, branching is a continuous by nexin/dynein regulatory complex (DRC) in- process matched only by the frequency of ex- terdoublet links (Fig. 1B). Ciliary assembly tinction, so trees need to be interpreted by imag- required trafficking on IFT complexes, the re- ining what has been lost as well as what remains sulting organelles possessed sensory capabilities (Jablonski 1986). The effects of horizontal gene maintained in part by Bardet–Beidl syndrome transfer can sometimes make trees look more (BBS) complex-dependent receptor traffick- like webs (Soucy et al. 2015), but most existing ing, and movement of transmembrane proteins eukaryotes fit into one of several major clades could be used for transport of material along the related primarily by their decent from a com- ciliary surface or gliding motility of the cell. In mon ancestor. These include the Stramenopiles, short, these cilia would have been structurally Alveolates, Rhizaria (SAR); the Plantae (proba- and functionally indistinguishable from typical bly a sister group to the SAR); the excavates cilia seen today. (Heterolobosea, Euglenozoa, Diplomonads), which may be more closely related to the SAR TUBULINS, DOUBLETS, AND TRIPLETS than to the Plantae; the Amoebozoa; and the opisthokonts (Fungi, Choanozoa, Metazoa), Phylogenomics showsthat this ciliated LECAex- which are more closely related to Amoebozoa pressed a-, b-, g-, d-, 1-, and z-tubulin (Dutcher than to the other clades. These branches appear 2003; Findeisen et al. 2014). a-, b-, and g-tubu- to have originated in an evolutionary big bang, lin areessentially universal in eukaryotes, where- probably about one billion years ago (Cherni- as d-,1-, andz-tubulins areonly found in species kova et al. 2011; Parfrey et al. 2011). Second, the with cilia. Although not all organisms with cilia last common ancestor of all of these branches retain all three of these more divergent tubulin was highly complex (Koumandou et al. 2013). isoforms, they occur in diverse taxa, supporting It had to have everything that is now found, in their presence in the LECA (see Azimzadeh at least some representatives, in every branch. 2014 and Turk et al. 2015 for other recent over- Based on features common to eukaryotes in all views of centrioles and tubulin diversity). d- of these clades, the LECA must have divided by and 1-tubulin have been implicated in forma- mitosis but also reproduced through a meiotic tion of basal bodies (Dutcher et al. 2002), and sexual cycle. It had a nucleus, endomembrane recent evidence suggests that z-tubulin is im- system, cytoskeleton, vesicular transport, mito- portant for formation of basal feet, structures chondria, and quite surely a cilium. equivalent to subdistal appendages, which or- Fortunately model organisms from distantly ganize interactions of basal bodies with other related branches have been used extensively in cell structures and maintain basal body orien- studies of ciliary structure, function, and bio- tation in multiciliated cells (Turk et al. 2015). chemistry, so that features common to the Perhaps one of the most elusive features of LECA and the extent of evolutionary change basal bodies is the way in which triplet micro- sincethat time can bereconstructed. Particularly tubules form. High-resolution electron micros- useful has been the intense focus on Trypa- copy of ciliary doublet (Nicastro et al. 2011; nosoma (excavata), Tetrahymena (SAR), Chla- Maheshwari et al. 2015) and basal body triplet mydomonas (plantae), and several metazoa microtubules (Li et al. 2012; Guichard and (opisthokonts). Based on features common to Gonczy 2016) has revealed not only the under- cilia in these distantly related organisms, the lying tubulin lattice structure but also many LECA had (most likely two) cilia with a typical nontubulin components, including structures 9þ2 architecture of outer doublet and central important for closing the walls of these doublet

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D.R. Mitchell

and triplet microtubules. The protein that Both ODA and I1 axonemal dyneins have het- forms one of these nontubulin “protofila- erodimeric intermediate chains. Sequence com- ments,” the elusive protofilament 11 that closes parisons suggest the formation first of an axo- the wall of the B-tubule, has recently been iden- nemal IC heterodimer, followed by a round of tified through a combined genetic and struc- duplication to create separate heterodimers for tural study in Chlamydomonas (Yanagisawa outer dynein arms and I1 inner dynein arms. et al. 2014). Equally elusive until relatively re- Interestingly, IFT dynein (unlike cytoplasmic cently was the basis for ninefold symmetry of dynein) appears to have heterodimeric interme- basal bodies, which depends on self-association diate chains that most closely resemble those of SAS-6 into a cartwheel (Kitagawa et al. 2011; of axonemal dyneins in the ODA-IC2 family van Breugel et al. 2011) and on its attachment to (Patel-King et al. 2013). A potential evolution- intertriplet linkers (Hiraki et al. 2007; for more ary pathway would start with a two-headed IFT on centriole assembly, see reviews by Azimza- dynein that had an IC2-like homodimer, fol- deh and Marshall 2010; Hirono 2014; Winey lowed by evolution of a two-headed axonemal and O’Toole 2014). dynein from association of IFT dynein heads More than a dozen phylogenetically wide- with a new heterodimeric IC base. This new spread nontubulin proteins have also been iden- base with its new IC1/IC2 heterodimer would tified as common components of centrioles allow IFT dynein to associate with A-tubules as and basal bodies, and many of these play specific cargoes and thus become the first axonemal dy- roles in centriolar assemblyor function (Hodges nein. Through a later duplication of the single et al. 2010; Carvalho-Santos et al. 2011). Others IC2-like IFT dynein intermediate chain gene, have a more limited phylogenetic distribution IFT dynein itself evolved to its present form and likely evolved to fill organism-specific func- with a base made from heterodimeric interme- tions. Despite a number of proteomic and tran- diate chains. scriptomic studies (Keller et al. 2005; Kilburn Outer dynein arms of the LECA were prob- et al. 2007; Fritz-Laylin and Cande 2010; Firat- ably anchored onto doublets with the aid of a Karalar et al. 2014) and genetic screens (Dobbe- docking complex made from a heterodimer of laere et al. 2008; Lin and Dutcher 2015), ad- coiled-coil proteins, based on localization stud- ditional proteins involved in evolutionarily ies and similarities between the phenotypes of conserved basal body functions likely remain vertebrate (Jerber et al. 2013; Knowles et al. to be discovered. 2013; Onoufriadis et al. 2013; Hjeij et al. 2014) and algal (Koutoulis et al. 1997; Takada et al. 2002) docking complex mutants. However, ho- MOTILITY mologs of one of the two proteins thought to Motility in cilia of the LECA would have been function as a docking complex in vertebrates generated by a two-headed outer row of dynein (CCDC151) is more closely related at the pri- arms (ODAs) and an inner row that had both a mary sequence level to a protein (ODA10) that two-headed inner dynein arm (similar to the I1 functions in outer dynein assembly rather than dynein of Chlamydomonas) and single-headed docking in the alga (Dean and Mitchell 2013, inner dynein arms (IDAs) generated from three 2015). Thus some caution is needed before all different heavy chain isoforms (Fig. 1B) (Wick- proteins identified on the basis of sequence sim- stead and Gull 2007; Wilkes et al. 2008). A pair ilarity are assumed to be functionally equivalent of WD-repeat-containing intermediate chains in different organisms, including the LECA. was likely associated with each of the two-head- Many additional proteins associated with axo- ed axonemal dyneins (Wickstead and Gull 2007; nemal dyneins in Chlamydomonas that pre- Patel-King et al. 2013). These intermediate sumably act as axonemal dynein cargo adaptors chains (ICs) were similar to, and likely evolved (Yamamoto et al. 2006, 2008) or regulatory from, the intermediate chain homodimers that complexes (Yamamoto et al. 2013) have easily are associated with all cytoplasmic dyneins. identified homologs in the genomes of other

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Evolution of Cilia

ciliated organisms (Hom et al. 2011), but direct 2015). Most of the known Chlamydomonas tests of their functional equivalency are lacking. DRC subunits have clear homologs in vertebrate As a further example of more recently acquired genomes, confirming the overall high level of diversity underlying apparent homology, regu- conservation of this complex (Bower et al. lation of ciliary motility by calcium-dependent 2013). modulation of outer dynein arm activity is The regulatory network supplied by inter- widespread, but the actual calcium sensors like- actions between the central-pair complex and ly evolved independently in different clades (In- radial spokes must also have evolved before aba 2015). the LECA, based on overall similarities between An interesting point of speculation is how central-pair complexes (Pigino et al. 2012; Car- the three single-headed IDAs expressed in the bajal-Gonzalez et al. 2013; Oda et al. 2014) and LECA (Wickstead and Gull 2007) were arranged radial spokes (Lin et al. 2012; Pigino et al. 2012) along the axoneme. Conservation of 96-nm pe- of sea urchin, Tetrahymena and Chlamydomo- riodicity (Oda et al. 2014) and of multiple struc- nas, as well as conservation of many central-pair tures associated with IDAs in such diverse or- and radial spoke proteins at the primary se- ganisms as Chlamydomonas and sea urchins quence level. We lack biochemical and genetic (Nicastro et al. 2006; O’Toole et al. 2012; Pigino data on the functions of many of these central- et al. 2012) argues for the presence in the LECA pair proteins, but continued exploration of mu- of not three, but six single-headed dyneins in tations that generate ciliary motility defects in each repeating unit (Fig. 1B). Perhaps future humans and in model organisms such as mice, studies of organisms with simplified genomes zebrafish, Trypanosoma, and Chlamydomonas that have reduced numbers of single-headed dy- promises further tests of functional as well as nein genes will provide clues to how three sin- sequence-level evolutionary conservation. gle-headed inner arm dyneins may have been anchored in these six sites in cilia of the LECA. TRAFFICKING, ASSEMBLY, AND SIGNALING Ancestral axonemal dyneins would have been regulated by at least three complexes The way in which cilia are assembled and main- (Fig. 1B): the modifier of inner arms (MIA) tained as segregated cytoplasmic and membrane complex associated with I1 dynein (Yamamoto compartments requires specialized docking of et al. 2013), the DRC/nexin link that joins ad- basal bodies to the plasma membrane through jacent doublets and likely transmits informa- interactions that involve the centriolar proximal tion about the extent or rate of interdoublet and distal appendages, and functions related to sliding (Heuser et al. 2009; Bower et al. 2013), endosomal trafficking. Once an axoneme begins and the radial spoke–central-pair complex that to assemble, transition zone components are may transmit information across the axoneme added that provide a selective barrier, and spe- and provide a more global level of control (Oda cialized transport systems are needed to supply et al. 2014). The MIA complex and interdoublet and retain material targeted to cilia. Many DRC/nexin links occur once every 96 nm along known components of each of these systems each doublet. They form interactions with mul- have been conserved in multiple eukaryotic tiple dyneins as well as with radial spokes clades and were therefore already present in (Heuser et al. 2009; Oda et al. 2015) and play the LECA. These include proteins associated important, if poorly understood, roles in dy- with distal appendages needed for membrane nein regulation. Similar links have been seen anchoring and structures such as basal feet by electron microscopy in motile cilia from and rootlets involved in anchoring motile cilia many diverse organisms, and mutations in in the cytoplasm (Carvalho-Santos et al. 2011). DRC subunits have been shown to alter the ac- IFT complexes and their associated dynein tivity of axonemal dyneins in Chlamydomonas and kinesin motors are needed both for assem- (Brokaw et al. 1982; Awata et al. 2015) and ver- bling the organelle and for maintaining its tebrates (Wirschell et al. 2013; Olbrich et al. normal length and composition in many di-

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verse species (Briggs et al. 2004; van Dam et al. RJL family of small G proteins (Elias and Archi- 2013). The gliding motility associated with fla- bald 2009) and some cyclic nucleotide-based gella in many single-celled eukaryotes likely de- sensory systems (Johnson and Leroux 2010; pends on IFTmotors as well (Collingridge et al. Sung and Leroux 2013), whereas prominent cil- 2013; Shih et al. 2013), although as yet direct ia-associated developmental signaling pathways analysis has unfortunately been limited to one such as Hedgehog are widespread among met- organism. The BBS complex, which plays a con- azoa, but not universally associated with cilia served role in maintaining normal concentra- (Roy 2012). tions of ciliary membrane-associated proteins, likely evolved from gene duplication and repur- EVOLUTIONARY TRENDS SINCE THE posing of IFT components, which in turn were DIVERGENCE OF EUKARYOTES derived from vesicle coat proteins (Satir et al. 2008; van Dam et al. 2013), before evolution Evolutionary change at the level of individual of the LECA. proteins or protein complexes, such as those Signaling pathways associated with ciliary providing the functional elements of cilia, can membranes have been modified extensively to be conceptually divided into simple categories. fit the needs of each organism or cell type, with Gene or whole genome duplication can result in relatively few signaling modules retained since multiple copies of slightly divergent proteins the LECA. One that appears to have associated that provide greater functional diversity, either with cilia comparatively early is the transient within one organelle or as a way to differentiate receptor potential (TRP) channel-linked me- organelles that provide unique abilities to a cell. chanical gating, including PKD1/2-like chan- Examples within an organelle include the fre- nels. In vertebrates, polycystic kidney disease quent expansion of the number of genes encod- (PKD) channels have been linked to signaling ing one or more of the three types of single- in embryonic nodal cilia (Field et al. 2011; Ka- headed IDAs. Different eukaryotic clades have mura et al. 2011; Yoshiba et al. 2012) as well as independently expanded the number of these in purely sensory cilia such as those in kidney single-headed axonemal dyneins, and at least tubules that give these proteins the PKD label in Chlamydomonas we know that this expansion (Nauli et al. 2003). In Chlamydomonas, a PKD2- results in a single cilium that uses multiple re- related TRP channel has been shown to play a lated dyneins within a single organelle, presum- role in the mating reaction, which involves ably to generate subtle levels of motility control adhesion-dependent ciliary signaling (Huang (Kamiya and Yagi2014). Even greater expansion et al. 2007), and similar channels are localized of the axonemal dynein family in some organ- to ciliary membranes in Paramecium (Valentine isms may allow assembly of cilia with unique et al. 2012). Chlamydomonas CAV2is a voltage- traits, such as the different cilia types present dependent calcium channel important for con- in the oral zone, body wall, and caudal region trol of waveform (Fujiu et al. 2009), and another of ciliates (Rajagopalan and Wilkes 2016), or Chlamydomonas TRPV-related protein, which the different cilia found on epithelia of mam- shows homology with the mechanosensitive malian airways, brain ventricles, fallopian tubes, Drosophila TRPV ciliary channels, is involved and the embryonic node. in ciliary mechanosensation (Fujiu et al. 2011). Alternatively, gene duplication can lead to The regulation of trafficking into this com- diversification into proteins used in very differ- partment by small G proteins of the Arl/Rab/ ent ways. Many proteins in cilia appear to be Arf family has been well documented in diverse more or less closely related to cytoplasmic pro- organisms, and must therefore have also been teins, but in some cases these proteins have present in the LECA (Sung and Leroux 2013). clearly acquired new functions quite indepen- Some other modules associated with trafficking dently in different eukaryotic clades, and were and signaling likely evolved in association with not likely present in cilia of the LECA. An ex- cilia before or soon after the LECA, such as the ample is the presence of metabolic enzymes

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Evolution of Cilia

involved in adenosine triphosphate (ATP) gen- through the two central singlets perpendicular eration. Mammalian sperm have glycolytic en- to the bend plane. In all members of the SAR or zymes and can use directly imported glucose for Plantae superclades, including ciliates, stra- ATP generation (Mukai and Okuno 2004), menopiles, and green algae, the central pair ro- whereas ATP concentrations in other cilia are tates during bend propagation so that, within maintained through phosphate shuttles (phos- each bend, a plane through the two central sin- phocreatine in sea urchin sperm [Tombes et al. glets is parallel to the bend plane (Omoto et al. 1987], phosphoarginine in Paramecium cilia 1999; Mitchell 2003; Mitchell and Nakatsugawa [Noguchi et al. 2001] and Trypanosoma flagella 2004). In organisms with a rotating central pair [Ooi et al. 2015]), or through independently this complex is inherently helical, twisting in acquired steps of the glycolytic pathway (Chla- interbend regions. Finally, in members of the mydomonas flagella [Mitchell et al. 2005]). Excavata superclade such as Euglena and Trypa- Equally commonly seen is the loss of pro- nosoma, central-pair orientation resembles that teins or structures, including cilia themselves, in unikonts, but is not as tightly fixed (Melko- when the energy inherent in maintaining such nian et al. 1982) and can “float” through as complexity is no longer needed. Examples in- much as 180˚ when released by mutations that clude the loss of IFT complexes in organisms affect flagellar motility (Branche et al. 2006; that only assemble cilia in the cytoplasm and Gadelha et al. 2006). Thus, rotation of a helical then extrude them preassembled (e.g., api- central pair is a synapomorphy of the SAR and complexans such as Plasmodium); loss of outer Plantae that supports the early branching of row (e.g., mosses and ferns) or inner row (dia- excavates before separation of these two super- toms) dyneins; and loss of the central-pair/ra- clades, whereas endosymbiosis of a plastid pre- dial spoke regulatory network (e.g., eel sperm, cursor occurred later, after their separation. mammalian nodal cilia). Comparative geno- mics backed by electron microscopy has also EVOLUTION OF CILIA BEFORE EUKARYOTIC shown that transition zone structures, essential DIVERGENCE for maintaining correct abundance of signaling modules on ciliary membranes (Li et al. 2016), Evolution of ciliary proteins in the pre-LECA era have been lost in some organisms (Barker et al. must have involved transformation of micro- 2014). tubule-based trafficking systems (single micro- Evolutionary changes in motility regulation tubules, cytoplasmic dynein and kinesin, and are more difficult to follow phylogenetically, but vesicle coat proteins) into cilia-specific forms one interesting case may add clarity to weakly (doublet microtubules, axonemal dyneins, IFT supported deep relationships among major eu- proteins). One view of this process starts with karyotic clades. Orientation of an asymmetric formation of doublet microtubules that act as central-pair complex has been linked to planar primitive centrioles, followed by evolution of beating of cilia. In many unrelated instances, mechanisms to dock a protocentriole to the loss of the central-pair has been correlated cell membrane and to extend the centriolar dou- with a switch to a circular or helical bending blet into a cilium-like structure (Marshall 2009). pattern, as seen in mammalian nodal cilia, eel Alternatively, projections of the cell membrane sperm, and the simplified cilia of some parasitic generated by assemblyof multiple singlet micro- protozoa (Satir et al. 2008). Although detailed tubules may have come first, and doublet for- structural comparisons support a remarkable mation may have evolved afterward (Satir et al. conservation of the central-pair complex, other 2008). In this latter scenario, microtubule-based evidence suggests that central-pair function membrane extensions function as both sensory changed in a dramatic way during divergence antennae and as gliding organelles, based on from the LECA (Fig. 1A). In all unikonts exam- properties common to cytoplasmic trafficking ined thus far, orientation of the central pair is by dyneins and kinesins. Doublets would evolve fixed along the length of the cilium, with a plane later, with the selective advantage deriving from

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D.R. Mitchell

their differentiation into two sides that can ed any traces of the previous evolutionary di- uniquely act as dynein cargos (A-tubules) and vergence of eukaryotes? Such an event could tracks (B-tubules) so that unidirectional bends have opened multiple ecological niches for rap- could form between doublet pairs. id expansion of the LECA into the major Many steps must have been needed to gen- branches represented by existing species. If so, erate the 600 or so proteins and 9þ2 architec- did this bottleneck result from a normal level of ture traceable to cilia of the LECA. Presumed fluctuation in a relatively small community of intermediate steps included trials of many alter- eukaryotic organisms (Fig. 2A), a cataclysmic native mechanisms of microtubule-based cell extinction event (Fig. 2B), or a sudden advan- motility, as well as more primitive versions of tage that appeared in only one lineage (Fig. 2C)? cilia, before a 9þ2 organelle appeared. The puz- The spectacular finding of Lokiarchaea and zle therefore is why no eukaryotes exist today their kin in deep sea vents has opened a new that descended from cells with any of these al- vista on the origins of eukaryotes (Spang et al. ternative proto-cilia. Why have no clades sur- 2015). These archaeal genomes reveal present- vived from earlier branches during the long evo- day organisms that have all the components lutionary period needed to get from the first needed for vesicular trafficking, including coat eukaryote common ancestor (FECA) to the proteins and small G proteins. However, these last common ancestor of all eukaryotes? Was trafficking components have not differentiated there an extreme bottleneck in eukaryotic evo- into the specific families of coat proteins (IFT lution at the time of the LECA, which eliminat- and BBS complex subunits) and G proteins

ABC Arch. Eukaryotes Bact. Arch. Eukaryotes Bact. Arch. Eukaryotes Bact. Present

Plastid Plastid Plastid LECA Mito Time

FECA Mito Mito HGT

LUCA Mito early, Mito early, random extinctions major extinction Mito late

Figure 2. Three alternative branching and extinction pathways leading from the last universal common ancestor (LUCA) to the first eukaryotic common ancestor (FECA), the last eukaryotic common ancestor (LECA), and present eukaryotic clades are diagrammed to explore mechanisms that selected for a LECA with 9þ2 cilia. (A) Mitochondrial (Mito) endosymbiosis early, together with formation of a nucleus, transforms an archaeum into the FECA. Present diversity results from random branching and extinction, and alternate ciliary architectures are lost by chance. (B) Mitochondria are acquired early. Present clades result from rapid divergence from the LECA following a major extinction event, which chanced to preserve an organism with 9þ2 cilia. (C) Horizontal gene transfer (HGT) between eubacteria and archaea generates an amitochondriate FECA. Much later, endosymbi- osis of an a-proteobacterium creates the LECA, which rapidly diverges into present clades, whereas clades that lack mitochondria become extinct. The host for endosymbiosis, by chance, has 9þ2 cilia. Arch., Archaea; Bact., bacteria.

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Evolution of Cilia

(Arls, Rabs, IFT22, IFT27) that are known to Mastigamoeba) genera, so mitochondrial-based function in ciliary trafficking. Likewise, Lo- ATPformation is not essential for a cell to main- kiarchaeotes have actin-related sequences, but tain flagellar function. Thus, an organism that lack canonical eukaryotic actin and Arps. The had already evolved a primitive cilium might available genomic sequences also lack homologs have had a selective advantage over competing of the GTPase-activating proteins (GAPs) and organisms when its motility was further en- guanine nucleotide exchange factors (GEFs) hanced by acquisition of an endosymbiotic that regulate trafficking in modern eukaryotes, a-proteobacterial power source. and, most important, have no obvious homo- logs of tubulin. Based on recent analysis of orthologous groups, proto-eukaryotes likely CONCLUDING REMARKS formed through acquisition of a large set of bac- The last eukaryotic common ancestor was a re- terial genes by an archaeote closely related to markably complex cell with motile cilia built on existing Lokiarchaeota, perhaps through multi- a typical 9þ2 microtubule array, capable of ple HGTs (Spang et al. 2015; Pittis and Gabal- gliding motility, beating motility, and display don 2016) as indicated in Figure 2C. Then, at a of sensory receptors. Genomic, metagenomic, much later time, endosymbiosis of an a proteo- and transcriptomic sequence analyses have re- bacterium in one descendant branch led to mi- vealed that most of the proteins present in cilia tochondrial formation (Pittis and Gabaldon today were also present in this common ances- 2016). The Big Bang of eukaryotic diversifica- tor, pushing the initial evolution of cilia into the tion, which probably occurred about one billion interval between divergence of eukaryotes from years ago, may thus have been stimulated by the archaeal prokaryotes and divergence of extant energetic and metabolic benefits conferred by eukaryotic clades beginning about one billion mitochondria (Lane 2014). years ago. Diversification into modern organ- Because eukaryotic tubulins are not specif- isms may be traced by relatively subtle changes ically more closely related to a-proteobacterial in ciliary architecture but by more radical tubulin homologs than to tubulin homologs changes in regulation of bending patterns and from other prokaryotes (Findeisen et al. 2014), by many instances of reduction or loss of cilia. an early HGT (perhaps one leading specifically Ciliary based signaling through sensory recep- to eukaryote formation, as in Fig. 2C) likely tors, although present ancestrally, has shown the included a bacterial FtsZ homolog that became greatest clade- and cell-type-specific expansion the ancestor of all tubulins. Duplication and in the repertoire of these versatile organelles. diversification resulted in the full repertoire of tubulins of the LECA. Multiple tubulin-based motility mechanisms may have coexisted in di- vergent pre-LECA branches, with dominance of REFERENCES 9þ2 cilia only occurring post-LECA. One ap- Awata J, Song K, Lin J, King SM, Sanderson MJ, Nicastro D, parent difficulty with this view is that if an ATP- Witman GB. 2015. DRC3 connects the N-DRC to dynein g to regulate flagellar waveform. Mol Biol Cell 26: 2788– rich intracellularenvironment is needed to drive 2800. ciliary motility (Chen et al. 2015), then mito- Azimzadeh J. 2014. Exploring the evolutionary history of chondria would need to already be present to centrosomes. Philos Trans R Soc Lond B Biol Sci 369: support evolutionary selection of an energy-de- 20130453. manding motility mechanism. However, al- Azimzadeh J, Marshall WF. 2010. Building the centriole. Curr Biol 20: R816–R825. though abundant ATP might have been neces- Barker AR, Renzaglia KS, Fry K, Dawe HR. 2014. Bioinfor- sary to support initial selection of the many matic analysis of ciliary transition zone proteins reveals steps needed during cilia evolution, flagellated insights into the evolution of ciliopathy networks. BMC anaerobic (and virtually amitochondriate) or- Genomics 15: 531. Bower R, Tritschler D, Vanderwaal K, Perrone CA, Mueller J, ganisms are known among both parasitic (e.g., Fox L, Sale WS, Porter ME. 2013. The N-DRC forms a Giardia) and free-living (e.g., Hexamita and conserved biochemical complex that maintains outer

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Evolution of Cilia

David R. Mitchell

Cold Spring Harb Perspect Biol 2017; doi: 10.1101/cshperspect.a028290 originally published online September 23, 2016

Subject Collection Cilia

Ciliary Mechanisms of Cyst Formation in Cilia in Left−Right Symmetry Breaking Polycystic Kidney Disease Kyosuke Shinohara and Hiroshi Hamada Ming Ma, Anna-Rachel Gallagher and Stefan Somlo Photoreceptor Cilia and Retinal Ciliopathies Discovery, Diagnosis, and Etiology of Craniofacial Kinga M. Bujakowska, Qin Liu and Eric A. Pierce Ciliopathies Elizabeth N. Schock and Samantha A. Brugmann G-Protein-Coupled Receptor Signaling in Cilia Axoneme Structure from Motile Cilia Kirk Mykytyn and Candice Askwith Takashi Ishikawa Evolution of Cilia Cilia and Ciliopathies in Congenital Heart Disease David R. Mitchell Nikolai T. Klena, Brian C. Gibbs and Cecilia W. Lo Transition Zone Migration: A Mechanism for Sperm Sensory Signaling Cytoplasmic Ciliogenesis and Postaxonemal Dagmar Wachten, Jan F. Jikeli and U. Benjamin Centriole Elongation Kaupp Tomer Avidor-Reiss, Andrew Ha and Marcus L. Basiri Cilia and Obesity Primary Cilia and Coordination of Receptor Christian Vaisse, Jeremy F. Reiter and Nicolas F. Tyrosine Kinase (RTK) and Transforming Growth Berbari Factor β (TGF-β) Signaling Søren T. Christensen, Stine K. Morthorst, Johanne B. Mogensen, et al. Posttranslational Modifications of Tubulin and Primary Cilia and Mammalian Hedgehog Signaling Cilia Fiona Bangs and Kathryn V. Anderson Dorota Wloga, Ewa Joachimiak, Panagiota Louka, et al.

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Radial Spokes−−A Snapshot of the Motility Cilia and Mucociliary Clearance Regulation, Assembly, and Evolution of Cilia and Ximena M. Bustamante-Marin and Lawrence E. Flagella Ostrowski Xiaoyan Zhu, Yi Liu and Pinfen Yang

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