Index

A cytoplasmic preassembly and trafficking AC. See Adenylate cyclase of complexes, 34–35 Adenylate cyclase (AC), sperm signaling, 278 dysfunction consequences, 38–39 ADPKD. See Autosomal-dominant polycystic motor function and regulation, 36, 38 kidney disease prospects for study, 39 Agouti-related peptide (AgRP), 259 bending mechanism, 11–12 AgRP. See Agouti-related peptide intermediate chain and light chain complexes, 12 AHI1, 351 isoform distribution, 12 AKAPs. See Protein kinase A–anchoring proteins nucleotide-induced structural change, 5 AKT, cilia signaling, 128–131 structure and arrangement, 4, 10–11 AKT1, 265 electron microscopy, 8–9 ALR13b, 232 exceptional motile cilia, 6–8 Alstrom syndrome, 230, 257, 259–260, 355 microtubule doublet AMPK, 265 linkers, 13 ANKS6, 225, 229 structure, 3, 6–10 Annulus 9þ2 structure, 3, 6, 9, 126 migration, 119–121 prospects for study, 13–14 structure, 119 radial spoke structure, 12–13 Arl3, 101 structural overview, 1–6 ARL13B, 101, 155 Autosomal-dominant polycystic kidney disease (ADPKD) B cilia-dependent cyst activation Bardet–Biedl syndrome (BBS), 230, 247, 257, 259–260, animal models, 244–245 354–355 cyst formation in other ciliopathies, 247 Basal body (BB) PC1 regulation, 251 amplification, 184–186 physiological function, 245 assembly prospects for study, 251–252 dynamics, 185, 187 signaling evolution, 188 b1-integrin, 249 molecular control, 187–188 cyclic AMP, 248 ciliary beat orientation, 191–192 Hedgehog signaling, 245, 247–248 docking and ciliogenesis Lkb1, 248 actin cytoskeleton role, 188–190 mitogen-activated protein kinase, 249 assembly, 190–191 mTOR, 248–249 docking, 190 platelet-derived growth factor, 249 BBS. See Bardet–Biedl syndrome ciliary dysfunction in cyst formation, 243–244 BBS10, 264 gene mutations, 242–244 BBS12, 264 mechanosensor hypothesis for polycystins in cilia, BBSome, intraflagellar transport protein roles 249–251 in transport, 79–80 overview, 241 b-Arrestin, 168, 174 Axoneme b1-Integrin, cilia-dependent cyst activation signaling, 249 central pair structure, 12–13 Bitter taste receptor (T2R), 175 dynein Bld10p, 48 arms BLD12,48 assembly in axonemal superstructure, BMPs. See Bone morphogenetic proteins 35–36 Bone morphogenetic proteins (BMPs), cilia signaling, composition, 32–34, 37 134–135

381 Index

C CNGK. See Cyclic nucleotide-gated potassium channel CA. See Central apparatus Cogan syndrome, 227–228 cAMP. See Cyclic AMP Congenital heart disease (CHD) CapZIP, 190 cilia and signaling CatSper, sperm signaling, 277–278, 281, 284 cell polarity specification and polarized cell Cby1, 93, 103 migration, 332–333 CCDC14, 302 ciliopathy-associated congenital heart disease, CCDC39, 35 335–336 CCDC40, 35 development role, 326–328 CCDC78, 188 gene mutations, 334–335 CCDC103, 35 left–right patterning, 333–334 CCDC151, 302, 372 Sonic hedgehog, 329 CCNO, multiciliated cell specification and transforming growth factor-b, 332 differentiation regulation, 184–185, 188 Wnt, 329, 332 Cdc123, 93 development of cardiovascular system, 324–325 Cdc41, 93 four-chamber perturbation, 324, 326 CDH23, 350 overview, 323–324 CDHR1, 348 prospects for study, 336–337 Celsr, 189 CP. See Central pair Central apparatus (CA) CP110, 93, 150, 190–191 assembly, 47–49 CPC1, 46–47, 51 composition, 45–47 CPLANE, 150 functions, 49–51 Craniofacial ciliopathies. See also specific diseases pathology, 51–52 ciliary dysfunction sensitivity, 310 prospects for study, 52 development structure, 43–45 cranial neural crest cells, 313–315 Central pair (CP), structure, 12–13 facial ectoderm, 315–316 Centriole neuroectoderm, 315 cell-cycle changes, 111–112 overview, 312–313 cilium relationship, 112 pharyngeal endoderm, 316 elongation before axoneme assembly, 112, 114 signaling in cilia hedgehog response regulation, 149 Hedgehog signaling, 316–318 sperm Wnt, 318–319 giant centrioles, 115–117 overview, 309–310 specialized centrioles, 115 pairwise combination of phenotypes, 311 Centriole and spindle-associated protein (CSAP), 23 prospects for study, 319–320 CEP63, 187–188 tables of diseases, 312–313 CEP78, 350 CSAP. See Centriole and spindle-associated protein Cep83, 93–94, 102 Cyclic AMP (cAMP) Cep89, 93 cilia-dependent cyst activation signaling, 248 Cep123, 93 sperm signaling, 278 CEP162, 121–122, 187 Cyclic nucleotide-gated potassium channel CEP164, 83–94, 102, 190 (CNGK), sperm signaling, 276, CEP250, 350 279–280 Cep290, 95, 97, 104, 118, 121, 227 Cyclin D1, 292 Cerl2, 207–209 CFAP54, 52 CG42699, 122 D CHD. See Congenital heart disease DAAM1, 188, 190 CIB2, 350 DEUP1, 187–188 Cilia-dependent cyst activation. See Autosomal- Dishevelled, 189, 192–193, 205 dominant polycystic kidney disease Diversin, 189 Ciliary nephronophthisis (NPHP), 95–97, 102 DNAH1, 302 CLRN1, 348–350 DNAH5, 302 C-MYB, multiciliated cell specification and DNAH11, 303 differentiation regulation, 184 DNAJB13, 121

382 Index

Dynein, axoneme GLI1, 151, 153 arms GLI2, 151, 153, 155 assembly in axonemal superstructure, 35–36 GLI3, 153, 155, 317 composition, 32–34, 37 GPCRs. See G-protein-coupled receptors cytoplasmic preassembly and trafficking of G-protein-coupled receptors (GPCRs). See also specific complexes, 34–35 ligands dysfunction consequences, 38–39 cholangiocyte cilia signaling, 172–173 motor function and regulation, 36, 38 cilia localization impact, 175–176 prospects for study, 39 ciliary localization, 168 bending mechanism, 11–12 hedgehog signaling modulation, 171 intermediate chain and light chain complexes, 12 motile cilia signaling, 175 isoform distribution, 12 neuron cilia signaling, 173–175 nucleotide-induced structural change, 5 olfactory receptor signaling, 167–170 structure and arrangement, 4, 10–11 opsin signaling, 169–171 DYXC1, 302 overview of signaling, 165–167 renal cilia signaling, 171–172 Guanylate cyclase (GC), sperm signaling, 274, 276, 278–279 E EGF. See Epidermal growth factor EHD1, 93 H EHD3, 93 HARS, 350 Ellis–van Revald syndrome, 156 HCN. See Hyperpolarization-activated and cyclic Epidermal growth factor (EGF), cilia signaling, 133 nucleotide-gated channel EVC, 156 HDAC6, 20 Evolution Hedgehog signaling. See also specific proteins basal body, 188 centriole and basal body protein regulation cilia of response, 149 eukaryote divergence cilia evolution after, 374–375 cell lineage determination of primary cilia evolution before, 375–377 in mouse embryo, 156–158 last eukaryotic common ancestor, 370–371 cell-type-specific differences and signaling motility, 372–373 modulation, 155–156 overview, 369–370 gene mutation effects, 147–149, 154–155 trafficking, assembly, and signaling, 373–374 pathway switching control, 153–154 tubulins, 371–372 requirement for signaling in all vertebrate tissues, radial spoke, 60–62 150–151 cilia-dependent cyst activation, 245, 247–248 craniofacial ciliopathies, 316–318 F developmental patterning, 144–145 FAP59, 35 G-protein-coupled receptors in signaling FAP172, 35 modulation, 171 FAP221, 51 intraflagellar transport protein regulation, 79, 154–155 FBB18, 34 peripheral cilia in metabolic regulation and obesity, Fbf1, 93 264–265 FGF. See Fibroblast growth factor Hepatocyte growth factor (HGF), cilia signaling, 133 Fibroblast growth factor (FGF), cilia signaling, 133 HGF. See Hepatocyte growth factor FLTP, 190 HSP40, 60, 62 FSCN2, 348 Hydin, 46–47 FTO, 258, 263–264 Hyperpolarization-activated and cyclic nucleotide- gated channel (HCN), sperm signaling, 276–277 G GC. See Guanylate cyclase Gdf1, 207 I GEMC1, multiciliated cell specification and IFT. See Intraflagellar transport differentiation regulation, 183–184 IGF-1. See Insulin-like growth factor 1

383 Index

Inpp5e, 94 Left–right asymmetry Insulin-like growth factor 1 (IGF-1), cilia signaling, cilia-driven fluid flow in mouse embryo, 203–205 132–133 clockwise rotation of mouse node cilia, 206–207 Intraflagellar transport (IFT) congenital heart disease and cilia role in patterning, history of study, 73–75 334 IFT-A complex fluid flow in symmetry breaking architecture, 82 calcium flux, 208 protein functions in complex formation Cerl2 messenger RNA asymmetry in flow and stability, 82–83 sensing, 208–209 IFT-B complex immotile colia as flow sensor, 207–208 architecture overview, 203 IFT-B1, 75–76 planar cell polarity, 205 IFT-B2, 76–78 prospects for study, 209 protein functions Leptin, 258–259, 262 BBSome transport, 79–80 LKB1, 248, 265 formation and stability, 78 LRP2, 334 Hedgehog signaling regulation, 79, 154–155 LRRC50, 3 membrane protein sorting at cilium, 80–81 transport of motility factors, 78–79 tubulin dimer and microtubule binding, 81–82 M turnaround at ciliary tip, 80 MAK, 348 motor protein interactions with IFT complexes, MAPK. See Mitogen-activated protein kinase 84–85 MC4R. See Melanocortin 4 receptor overview, 71–73, 127 MCC. See Mucociliary clearance; Multiciliated cell photoreceptor sensory cilia, 343, 347 MCIDAS, multiciliated cell specification and prospects for study, 85 differentiation regulation, 183–184, 187 protein nomenclature, 74 MCKD. See Medullary–cystic kidney disease Sonic hedgehog signal transduction in mouse MEC-17/ATAT1, 18, 20 embryo, 145–146, 149 Meckel–Gruber syndrome (MKS), 229–230, 247, train formation and IFT-A/IFT-B complex 353–354 interactions, 83 Medullary–cystic kidney disease (MCKD), 214, 223 INVS, 225 Melanocortin 4 receptor (MC4R), 258–259 IQCB1, 227 Microtubule doublet (MTD) IRX3, 264 linkers, 13 structure, 3, 6–10 Mitogen-activated protein kinase (MAPK) J cilia-dependent cyst activation signaling, 249 JBTS4, 228 cilia signaling, 128–130 JBTS6, 228 MKS. See Meckel–Gruber syndrome JBTS7, 228 MKS complex, 95, 103 JBTS10, 230 MORM syndrome, 355 Joubert syndrome, 228, 247, 353 MTD. See Microtubule doublet mTOR, cilia-dependent cyst activation signaling, K 248–249 KAP3, 145 MUC1, 223 Kif17, 101 Mucociliary clearance (MCC) KIF3, 145, 149 cilia Kinesin-1, 20 beat frequency, 299–300 Kinesin-2, 127 regulation, 299–300 KISS1R, 175 structure, 297–299 KLP1, 46–47 components mucous layer, 295, 297 overview, 295–296 L periciliary layer, 297 Last eukaryotic common ancestor. See Evolution surfactant, 297 LCA5, 348 measurement

384 Index

overview, 300–301 therapy and prognosis, 225 variables, 301–302 type 1 disease, 231 overview, 291–292 type 2 disease, 224 primary ciliary dyskinesia, 302–303 Neuropeptide Y (NPY), 173 prospects for study, 303 NF-kB. See Nuclear factor-kB respiratory tract NHE. See Sodium/proton exchanger cell types in lower respiratory tract Nmyc, 292 ciliated cells, 294–295 Nodal, 207–208 secretory cells, 294 Notch, multiciliated cell specification and development, 292 differentiation regulation, 182–183 structure, 293–294 NPHP. See Ciliary nephronophthisis; Multiciliated cell (MCC) Nephronophthisis ciliary beat orientation NPHP1, 228, 231 basal body organization, 191–192 NPHP2, 228–229 beat regulation, 194–195 NPHP3, 228–229, 232, 244 hydrodynamic forces, 194 NPHP4, 189, 228, 231 polarization by planar cell polarity pathway, NPHP5, 227 192–194 NPHP6, 227 ciliogenesis. See Basal body NPHP7, 231 mammalian epithelia, 182 NPHP9, 244 overview, 181–182 NPY. See Neuropeptide Y prospects for study, 195 Nubp1, 190 specification and differentiation Nuclear factor-kB (NF-kB), cilia signaling, 134 downstream effectors, 184–185 GEMC1 regulation, 183–184 MCIDAS regulation, 183–184 O Notch inhibition, 182–183 Obesity MYO7A, 350 ciliopathies with obesity conditional mutants in mice, 260 LEPR mutations, 262 N mouse models, 260–261 NDK5, 60–61 neuron involvement, 260, 262–263 NEK8, 229 overview, 259–260 Nephronophthisis (NPHP) genetic predisposition, 258 cilia-dependent cyst activation, 247 leptin–melanocortin pathway regulation of energy clinical presentation, 224–225 homeostasis, 258–259 diagnosis, 226 pathophysiology, 258 differential diagnosis, 226 peripheral cilia in metabolic regulation and obesity, extrarenal manifestations 264–265 Alstrom syndrome, 230 prospects for study, 265–266 Bardet–Biedl syndrome, 230 RPBRIP1L studies, 263–264 Cogan syndrome, 227–228 ODA proteins, 34 congenital heart disease, 229 ODF2, 191 Joubert syndrome, 228 Odf2, 93 liver involvement, 228–229 OFD1. See Oral-facial-digital syndrome type 1 Meckel–Gruber syndrome, 229–230 Olfactory receptor, signaling, 167–170 oral-facial-digital syndrome type 1, 230 Opsins, vision signaling, 169–171 overview, 226–227 Oral-facial-digital syndrome type 1 (OFD1), 93, 150, Senior–Løken syndrome, 227 230, 355–356 skeletal phenotypes and polydactyly, 229 Usher syndrome, 230–231 genetics, 231 P genotype–phenotype correlations, 215–223 Patched1, 127–128, 143, 153–154 model organisms, 231–232 PCD. See Primary ciliary dyskinesia overview, 214, 223 PCDH15, 350 pathology, 225–226 PCP. See Planar cell polarity

385 Index

Pde6d, 101 R PDGF. See Platelet-derived growth factor Radial spoke (RS) PF proteins, 45–50 assembly, 62–63 Phosphoinositide 3-kinase (PI3K), cilia signaling, evolution, 60–62 128–130 functions Phospholipase C (PLC), cilia signaling, 129–130 axoneme stability maintenance, 65–66 Photoreceptor sensory cilia (PSC) chemical signaling, 65 functional overview, 341–342 mechanical feedback and coordination outer segment components, 343 of molecular motors, 64–65 protein transport planar waveform generation, 64 intraflagellar transport, 343, 347 morphology, 58 membrane protein transport, 347 mutants, 63 photoactivated protein diffusion, 347 outer doublet connections, 63 retinal ciliopathies periodicity, 58 Alstrom syndrome, 355 prospects for study, 66 Bardet–Biedl syndrome, 354–355 proteins genetic modifiers, 351–352, 355–356 Chlamydomonas, 58–60 Joubert syndrome, 353 organization, 60 Meckel–Gruber syndrome, 353–354 structure, 12–13, 59 MORM syndrome, 355 Receptor tyrosine kinase signaling. See specific ligands nonsyndromic retinal degeneration ROM1, 348 genes, 344–346 RP1, 348, 356 sensory function defects, 349–350 RPBRIP1L, 263–264 structural disruption, 348–349 Rpgrip1l, 96–97, 103–104, 257–258 oral-facial-digital syndrome, 355–356 RPIL1, 348 phenotypic spectrum, 355–356 RS. See Radial spoke Senior–Løken syndrome, 353 RSPH1, 302–303 short-rib thoracic dysplasia, 355 RSPH19, 302 Usher syndrome, 350, 353 RSPH4A, 302 structure, 342–343 PI3K. See Phosphoinositide 3-kinase PKA. See Protein kinase A S PKD1, 232, 242–243 SAS4, 149 PKD1, 349, 374 SAS-6, 187 PKD2, 232, 242–243 Senior–Løken syndrome (SLS), 227, 353 PKD2, 208, 349, 374 SHH. See Sonic hedgehog Pkd111, 208 Short-rib thoracic dysplasia (SRTD), 355 Pkd2l1, 175 SIRT2, 20 Planar cell polarity (PCP), 189, 192–194, 205 Slo3, 283 Platelet-derived growth factor (PDGF) SLS. See Senior–Løken syndrome cilia-dependent cyst activation signaling, 249 SMADs, cilia signaling, 134–136 cilia signaling, 129–132 SMO. See Smoothened PLC. See Phospholipase C Smoothened (SMO), 127–128, 143, 151, 247, 264 PLK4, 187 Sodium/proton exchanger (NHE), sperm signaling, Polycystic kidney disease. See Autosomal-dominant 276, 280 polycystic kidney disease Sonic hedgehog (SHH) Prickle, 189, 205 cilia signaling, 127–128 Primary ciliary dyskinesia (PCD) congenital heart disease and cilia signaling, 329 dynein arm dysfunction, 39 craniofacial ciliopathies, 316–318 gene mutations, 302–303 developmental patterning, 145 PROM1, 348 intraflagellar transport and signal transduction Protein kinase A (PKA), 153, 173 in mouse embryo, 145–146, 149 Protein kinase A–anchoring proteins (AKAPs), Sox9, 292 RSP3 as, 60 SPAG1, 302 PRPH2, 348, 356 Spag16L, 52 PSC. See Photoreceptor sensory cilia Spag17, 51

386 Index

Sperm cytoplasmic ciliogenesis annulus, 119–121 annulus in mammalian sperm, 119–121 guidance to egg, 271–273 axoneme exposure to cytoplasm, 117–118 signaling ciliary gate elasticity, 122 fish sperm, 279–280 Drosophila spermatids, 118–119 mammalian sperm motor-driven versus exchange-driven calcium clearance, 283–284 migration, 121 CatSper, 281, 283 Drosophila spermatocytes, 117–119 compartmentalization and supramolecular overview, 91–92 structures, 284–285 protein trafficking role intracellular pH regulation, 284 membrane proteins, 100–102 mouse versus human sperm, 282 soluble proteins, 98–100 overview, 280 TTBK2, 94, 150, 190 potassium channels, 283 TTC8, 355 prospects for study, 285 TTL. See Tubulin tyrosine ligase sea urchin sperm Tubulin adenylate cyclase, 278 cilia evolution, 371–372 amplification, 278–279 posttranslational modification CatSper, 277–278 acetylation of K40 cyclic nucleotide-gated potassium channel, cilia disassembly role, 20 276, 279 motor-driven motility role, 20–21 guanylate cyclase, 274, 276, 278–279 overview, 17–20 hyperpolarization-activated and cyclic detyrosination, 21 nucleotide-gated channel, 276–277 glutamylation overview, 274–275 ciliary assembly and microtubule stability recovery, 278 role, 23 sodium/proton exchanger, 276 motility role, 22–23 specialized centrioles and cilia, 115–117 negative length regulation of cilia, 23–24 SRTD. See Short-rib thoracic dysplasia overview, 21–22 SSTR3, 174–175 glycation, 24–25 SUFU, 158 overview, 17 prospects for study, 25 Tubulin tyrosine ligase (TTL), 21–25 T TULP1, 348 T2R. See Bitter taste receptor TULP3, 83, 154–155, 158 TAK1, 134 TZ. See Transition zone Talpid3, 150 Tctex-1, 133 TF. See Transition fiber U TGF-b. See Transforming growth factor b UMOD, 223 TGR5, 173 Unc119b, 101 Tie receptors, 133 USH1C, 350 Transforming growth factor b (TGF-b) USH1G, 350 cilia signaling, 133–137 USH2A, 348–350 congenital heart disease and cilia signaling, 332 Usher syndrome, 230–231 Transition fiber (TF) architecture, 92–93 V ciliary gate diseases, 102–104 Vangl, 189, 205 functions, 93–94 Vangl1, 192 overview, 91–92 Vangl2, 192 Transition zone (TZ) architecture, 94–96 ciliary gate diseases, 102–104 W ciliogenesis role, 97–98 WNT cilium compartmentalization, 114–115 cilia signaling, 128 migration congenital heart disease and cilia signaling, 329, 332 centriole formation and ciliogenesis, 112–113 craniofacial ciliopathies, 318–319

387