Primary cilia in hard tissue development and diseases

Abstract

Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.

Keywords

primary cilia / bone / mechanical sensing / hard tissue / cilium-related bone disease / tooth

References

[1] Berendsen AD, Olsen BR. Bone development. Bone 2015; 80: 14–18

[2] Buck DW 2nd, Dumanian GA. Bone biology and physiology: part I. The fundamentals. Plast Reconstr Surg 2012; 129(6): 1314–1320

[3] Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci 2006; 1092(1): 385–396

[4] Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008; 3(Suppl 3): S131–S139

[5] Owen M. The origin of bone cells in the postnatal organism. Arthritis Rheum 1980; 23(10): 1073–1080

[6] Walmsley GG, Ransom RC, Zielins ER, Leavitt T, Flacco JS, Hu MS, Lee AS, Longaker MT, Wan DC. Stem cells in bone regeneration. Stem Cell Rev Rep 2016; 12(5): 524–529

[7] Scherft JP, Daems WT. Single cilia in chondrocytes. J Ultrastruct Res 1967; 19(5): 546–555

[8] Rich DR, Clark AL. Chondrocyte primary cilia shorten in response to osmotic challenge and are sites for endocytosis. Osteoarthritis Cartilage 2012; 20(8): 923–930

[9] Wang S, Wei Q, Dong G, Dong Z. ERK-mediated suppression of cilia in cisplatin-induced tubular cell apoptosis and acute kidney injury. Biochim Biophys Acta 2013; 1832(10): 1582–1590

[10] Tummala P, Arnsdorf EJ, Jacobs CR. The role of primary cilia in mesenchymal stem cell differentiation: a pivotal switch in guiding lineage commitment. Cell Mol Bioeng 2010; 3(3): 207–212

[11] Xiao Z, Zhang S, Mahlios J, Zhou G, Magenheimer BS, Guo D, Dallas SL, Maser R, Calvet JP, Bonewald L, Quarles LD. Cilia-like structures and polycystin-1 in osteoblasts/osteocytes and associated abnormalities in skeletogenesis and Runx2 expression. J Biol Chem 2006; 281(41): 30884–30895

[12] Malone AM, Anderson CT, Tummala P, Kwon RY, Johnston TR, Stearns T, Jacobs CR. Primary cilia mediate mechanosensing in bone cells by a calcium-independent mechanism. Proc Natl Acad Sci U S A 2007; 104(33): 13325–13330

[13] Federman M, Nichols G Jr. Bone cell cilia: vestigial or functional organelles? Calcif Tissue Res 1974; 17(1): 81–85

[14] Yuan X, Serra RA, Yang S. Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton. Ann N Y Acad Sci 2015; 1335(1): 78–99

[15] Eggenschwiler JT, Anderson KV. Cilia and developmental signaling. Annu Rev Cell Dev Biol 2007; 23(1): 345–373

[16] Fry AM, Leaper MJ, Bayliss R. The primary cilium: guardian of organ development and homeostasis. Organogenesis 2014; 10(1): 62–68

[17] Sorokin SP. Reconstructions of centriole formation and ciliogenesis in mammalian lungs. J Cell Sci 1968; 3(2): 207–230

[18] Berbari NF, O’Connor AK, Haycraft CJ, Yoder BK. The primary cilium as a complex signaling center. Curr Biol 2009; 19(13): R526–R535

[19] Izawa I, Goto H, Kasahara K, Inagaki M. Current topics of functional links between primary cilia and cell cycle. Cilia 2015; 4(1): 12

[20] Wheway G, Nazlamova L, Hancock JT. Signaling through the primary cilium. Front Cell Dev Biol 2018; 6: 8

[21] Satir P, Christensen ST. Overview of structure and function of mammalian cilia. Annu Rev Physiol 2007; 69(1): 377–400

[22] Youn YH, Han YG. Primary cilia in brain development and diseases. Am J Pathol 2018; 188(1): 11–22

[23] Desai A, Mitchison TJ. Microtubule polymerization dynamics. Annu Rev Cell Dev Biol 1997; 13(1): 83–117

[24] Yoon SY, Choi JE, Choi JM, Kim DH. Dynein cleavage and microtubule accumulation in okadaic acid-treated neurons. Neurosci Lett 2008; 437(2): 111–115

[25] Kim S, Zaghloul NA, Bubenshchikova E, Oh EC, Rankin S, Katsanis N, Obara T, Tsiokas L. Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry. Nat Cell Biol 2011; 13(4): 351–360

[26] Cao M, Zhong Q. Cilia in autophagy and cancer. Cilia 2016; 5(1): 4

[27] Hu Q, Nelson WJ. Ciliary diffusion barrier: the gatekeeper for the primary cilium compartment. Cytoskeleton (Hoboken) 2011; 68(6): 313–324

[28] Christopher KJ, Wang B, Kong Y, Weatherbee SD. Forward genetics uncovers transmembrane protein 107 as a novel factor required for ciliogenesis and Sonic hedgehog signaling. Dev Biol 2012; 368(2): 382–392

[29] Satir P, Pedersen LB, Christensen ST. The primary cilium at a glance. J Cell Sci 2010; 123(4): 499–503

[30] Rosenbaum JL, Witman GB. Intraflagellar transport. Nat Rev Mol Cell Biol 2002; 3(11): 813–825

[31] Yang S, Wang C. The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis. Bone 2012; 51(3): 407–417

[32] Veland IR, Awan A, Pedersen LB, Yoder BK, Christensen ST. Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol 2009; 111(3): 39–53

[33] Yuan X, Yang S. Primary cilia and intraflagellar transport proteins in bone and cartilage. J Dent Res 2016; 95(12): 1341–1349

[34] Goetz SC, Ocbina PJ, Anderson KV. The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol 2009; 94: 199–222

[35] Cai S, Bodle JC, Mathieu PS, Amos A, Hamouda M, Bernacki S, McCarty G, Loboa EG. Primary cilia are sensors of electrical field stimulation to induce osteogenesis of human adipose-derived stem cells. FASEB J 2017; 31(1): 346–355

[36] McMurray RJ, Wann AK, Thompson CL, Connelly JT, Knight MM. Surface topography regulates wnt signaling through control of primary cilia structure in mesenchymal stem cells. Sci Rep 2013; 3(1): 3545

[37] Yuan X, Cao J, He X, Serra R, Qu J, Cao X, Yang S. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation. Nat Commun 2016; 7(1): 11024

[38] Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet 2012; 160C(3): 165–174

[39] Day TF, Yang Y. Wnt and hedgehog signaling pathways in bone development. J Bone Joint Surg Am 2008; 90(Suppl 1): 19–24

[40] Rohatgi R, Milenkovic L, Scott MP. Patched1 regulates hedgehog signaling at the primary cilium. Science 2007; 317(5836): 372–376

[41] Haycraft CJ, Zhang Q, Song B, Jackson WS, Detloff PJ, Serra R, Yoder BK. Intraflagellar transport is essential for endochondral bone formation. Development 2007; 134(2): 307–316

[42] Kikuchi A, Yamamoto H. Tumor formation due to abnormalities in the β-catenin-independent pathway of Wnt signaling. Cancer Sci 2008; 99(2): 202–208

[43] Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 2013; 19(2): 179–192

[44] Lancaster MA, Schroth J, Gleeson JG. Subcellular spatial regulation of canonical Wnt signalling at the primary cilium. Nat Cell Biol 2011; 13(6): 700–707

[45] Corrigan MA, Ferradaes TM, Riffault M, Hoey DA. Ciliotherapy treatments to enhance biochemically- and biophysically-induced mesenchymal stem cell osteogenesis: a comparison study. Cell Mol Bioeng 2018; 12(1): 53–67

[46] Corbit KC, Shyer AE, Dowdle WE, Gaulden J, Singla V, Chen MH, Chuang PT, Reiter JF. Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 2008; 10(1): 70–76

[47] Lienkamp S, Ganner A, Walz G. Inversin, Wnt signaling and primary cilia. Differentiation 2012; 83(2): S49–S55

[48] Pitaval A, Tseng Q, Bornens M, Théry M. Cell shape and contractility regulate ciliogenesis in cell cycle-arrested cells. J Cell Biol 2010; 191(2): 303–312

[49] Li A, Xia X, Yeh J, Kua H, Liu H, Mishina Y, Hao A, Li B. PDGF-AA promotes osteogenic differentiation and migration of mesenchymal stem cell by down-regulating PDGFRα and derepressing BMP-Smad1/5/8 signaling. PLoS One 2014; 9(12): e113785

[50] Schmid FM, Schou KB, Vilhelm MJ, Holm MS, Breslin L, Farinelli P, Larsen LA, Andersen JS, Pedersen LB, Christensen ST. IFT20 modulates ciliary PDGFRα signaling by regulating the stability of Cbl E3 ubiquitin ligases. J Cell Biol 2018; 217(1): 151–161

[51] Graham S, Leonidou A, Lester M, Heliotis M, Mantalaris A, Tsiridis E. Investigating the role of PDGF as a potential drug therapy in bone formation and fracture healing. Expert Opin Investig Drugs 2009; 18(11): 1633–1654

[52] Noda K, Kitami M, Kitami K, Kaku M, Komatsu Y. Canonical and noncanonical intraflagellar transport regulates craniofacial skeletal development. Proc Natl Acad Sci U S A 2016; 113(19): E2589–E2597

[53] Schneider L, Clement CA, Teilmann SC, Pazour GJ, Hoffmann EK, Satir P, Christensen ST. PDGFRαα signaling is regulated through the primary cilium in fibroblasts. Curr Biol 2005; 15(20): 1861–1866

[54] Umberger NL, Caspary T, Bettencourt-Dias M. Ciliary transport regulates PDGF-AA/αα signaling via elevated mammalian target of rapamycin signaling and diminished PP2A activity. Mol Biol Cell 2015; 26(2): 350–358

[55] Poniatowski ŁA, Wojdasiewicz P, Gasik R, Szukiewicz D. Transforming growth factor β family: insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediators Inflamm 2015; 2015: 137823

[56] Anvarian Z, Mykytyn K, Mukhopadhyay S, Pedersen LB, Christensen ST. Cellular signalling by primary cilia in development, organ function and disease. Nat Rev Nephrol 2019; 15(4): 199–219

[57] Moore ER, Jacobs CR. The primary cilium as a signaling nexus for growth plate function and subsequent skeletal development. J Orthop Res 2018; 36(2): 533–545

[58] Liu M, Alharbi M, Graves D, Yang S. IFT80 is required for fracture healing through controlling the regulation of TGF-β signaling in chondrocyte differentiation and function. J Bone Miner Res 2020; 35(3): 571–582

[59] Aspera-Werz RH, Chen T, Ehnert S, Zhu S, Fröhlich T, Nussler AK. Cigarette smoke induces the risk of metabolic bone diseases: transforming growth factor β signaling impairment via dysfunctional primary cilia affects migration, proliferation, and differentiation of human mesenchymal stem cells. Int J Mol Sci 2019; 20(12): 2915

[60] Xie YF, Shi WG, Zhou J, Gao YH, Li SF, Fang QQ, Wang MG, Ma HP, Wang JF, Xian CJ, Chen KM. Pulsed electromagnetic fields stimulate osteogenic differentiation and maturation of osteoblasts by upregulating the expression of BMPRII localized at the base of primary cilium. Bone 2016; 93: 22–32

[61] Labour MN, Riffault M, Christensen ST, Hoey DA. TGFβ1-induced recruitment of human bone mesenchymal stem cells is mediated by the primary cilium in a SMAD3-dependent manner. Sci Rep 2016; 6(1): 35542

[62] Uzbekov RE, Maurel DB, Aveline PC, Pallu S, Benhamou CL, Rochefort GY. Centrosome fine ultrastructure of the osteocyte mechanosensitive primary cilium. Microsc Microanal 2012; 18(6): 1430–1441

[63] Sharma D, Ciani C, Marin PA, Levy JD, Doty SB, Fritton SP. Alterations in the osteocyte lacunar-canalicular microenvironment due to estrogen deficiency. Bone 2012; 51(3): 488–497

[64] Main RP. Osteocytes and the bone lacunar-canalicular system: insights into bone biology and skeletal function using bone tissue microstructure. Int J Paleopathol 2017; 18: 44–46

[65] Gurkan UA, Akkus O. The mechanical environment of bone marrow: a review. Ann Biomed Eng 2008; 36(12): 1978–1991

[66] Whitfield JF. Primary cilium—is it an osteocyte’s strain-sensing flowmeter? J Cell Biochem 2003; 89(2): 233–237

[67] Pavalko FM, Norvell SM, Burr DB, Turner CH, Duncan RL, Bidwell JP. A model for mechanotransduction in bone cells: the load-bearing mechanosomes. J Cell Biochem 2003; 88(1): 104–112

[68] Bonewald LF. Mechanosensation and transduction in osteocytes. Bonekey Osteovision 2006; 3(10): 7–15

[69] Stavenschi E, Labour MN, Hoey DA. Oscillatory fluid flow induces the osteogenic lineage commitment of mesenchymal stem cells: the effect of shear stress magnitude, frequency, and duration. J Biomech 2017; 55: 99–106

[70] Riddle RC, Taylor AF, Genetos DC, Donahue HJ. MAP kinase and calcium signaling mediate fluid flow-induced human mesenchymal stem cell proliferation. Am J Physiol Cell Physiol 2006; 290(3): C776–C784

[71] Metzger TA, Kreipke TC, Vaughan TJ, McNamara LM, Niebur GL. The in situ mechanics of trabecular bone marrow: the potential for mechanobiological response. J Biomech Eng 2015; 137(1): 011006

[72] Hu K, Sun H, Gui B, Sui C. TRPV4 functions in flow shear stress induced early osteogenic differentiation of human bone marrow mesenchymal stem cells. Biomed Pharmacother 2017; 91: 841–848

[73] Yourek G, McCormick SM, Mao JJ, Reilly GC. Shear stress induces osteogenic differentiation of human mesenchymal stem cells. Regen Med 2010; 5(5): 713–724

[74] Sonam S, Sathe SR, Yim EK, Sheetz MP, Lim CT. Cell contractility arising from topography and shear flow determines human mesenchymal stem cell fate. Sci Rep 2016; 6(1): 20415

[75] Shi W, Zhang Y, Chen K, He J, Feng X, Wei W, Hua J, Wang J. Primary cilia act as microgravity sensors by depolymerizing microtubules to inhibit osteoblastic differentiation and mineralization. Bone 2020; 136: 115346

[76] Praetorius HA, Spring KR. Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 2001; 184(1): 71–79

[77] Uda Y, Azab E, Sun N, Shi C, Pajevic PD. Osteocyte mechanobiology. Curr Osteoporos Rep 2017; 15(4): 318–325

[78] Chen JC, Hoey DA, Chua M, Bellon R, Jacobs CR. Mechanical signals promote osteogenic fate through a primary cilia-mediated mechanism. FASEB J 2016; 30(4): 1504–1511

[79] Moore ER, Zhu YX, Ryu HS, Jacobs CR. Periosteal progenitors contribute to load-induced bone formation in adult mice and require primary cilia to sense mechanical stimulation. Stem Cell Res Ther 2018; 9(1): 190

[80] Kitase Y, Barragan L, Qing H, Kondoh S, Jiang JX, Johnson ML, Bonewald LF. Mechanical induction of PGE2 in osteocytes blocks glucocorticoid-induced apoptosis through both the β-catenin and PKA pathways. J Bone Miner Res 2010; 25(12): 2657–2668

[81] Delaine-Smith RM, Sittichokechaiwut A, Reilly GC. Primary cilia respond to fluid shear stress and mediate flow-induced calcium deposition in osteoblasts. FASEB J 2014; 28(1): 430–439

[82] Kaku M, Komatsu Y. Functional diversity of ciliary proteins in bone development and disease. Curr Osteoporos Rep 2017; 15(2): 96–102

[83] Liu W, Xu S, Woda C, Kim P, Weinbaum S, Satlin LM. Effect of flow and stretch on the [Ca²⁺]i response of principal and intercalated cells in cortical collecting duct. Am J Physiol Renal Physiol 2003; 285(5): F998–F1012

[84] McGlashan SR, Knight MM, Chowdhury TT, Joshi P, Jensen CG, Kennedy S, Poole CA. Mechanical loading modulates chondrocyte primary cilia incidence and length. Cell Biol Int 2010; 34(5): 441–446

[85] Gardner K, Arnoczky SP, Lavagnino M. Effect of in vitro stress-deprivation and cyclic loading on the length of tendon cell cilia in situ. J Orthop Res 2011; 29(4): 582–587

[86] Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci U S A 2003; 100(9): 5286–5291

[87] Qiu N, Xiao Z, Cao L, Buechel MM, David V, Roan E, Quarles LD. Disruption of Kif3a in osteoblasts results in defective bone formation and osteopenia. J Cell Sci 2012; 125(8): 1945–1957

[88] Kolpakova-Hart E, Jinnin M, Hou B, Fukai N, Olsen BR. Kinesin-2 controls development and patterning of the vertebrate skeleton by Hedgehog- and Gli3-dependent mechanisms. Dev Biol 2007; 309(2): 273–284

[89] Temiyasathit S, Tang WJ, Leucht P, Anderson CT, Monica SD, Castillo AB, Helms JA, Stearns T, Jacobs CR. Mechanosensing by the primary cilium: deletion of Kif3A reduces bone formation due to loading. PLoS One 2012; 7(3): e33368

[90] Leucht P, Monica SD, Temiyasathit S, Lenton K, Manu A, Longaker MT, Jacobs CR, Spilker RL, Guo H, Brunski JB, Helms JA. Primary cilia act as mechanosensors during bone healing around an implant. Med Eng Phys 2013; 35(3): 392–402

[91] Li H. TRP channel classification. Adv Exp Med Biol 2017; 976: 1–8

[92] Siroky BJ, Kleene NK, Kleene SJ, Varnell CD Jr, Comer RG, Liu J, Lu L, Pachciarz NW, Bissler JJ, Dixon BP. Primary cilia regulate the osmotic stress response of renal epithelial cells through TRPM3. Am J Physiol Renal Physiol 2017; 312(4): F791–F805

[93] Corrigan MA, Johnson GP, Stavenschi E, Riffault M, Labour MN, Hoey DA. TRPV4-mediates oscillatory fluid shear mechanotransduction in mesenchymal stem cells in part via the primary cilium. Sci Rep 2018; 8(1): 3824

[94] Mizoguchi F, Mizuno A, Hayata T, Nakashima K, Heller S, Ushida T, Sokabe M, Miyasaka N, Suzuki M, Ezura Y, Noda M. Transient receptor potential vanilloid 4 deficiency suppresses unloading-induced bone loss. J Cell Physiol 2008; 216(1): 47–53

[95] Masuyama R, Vriens J, Voets T, Karashima Y, Owsianik G, Vennekens R, Lieben L, Torrekens S, Moermans K, Vanden Bosch A, Bouillon R, Nilius B, Carmeliet G. TRPV4-mediated calcium influx regulates terminal differentiation of osteoclasts. Cell Metab 2008; 8(3): 257–265

[96] Winslow MM, Pan M, Starbuck M, Gallo EM, Deng L, Karsenty G, Crabtree GR. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell 2006; 10(6): 771–782

[97] Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, Saiura A, Isobe M, Yokochi T, Inoue J, Wagner EF, Mak TW, Kodama T, Taniguchi T. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell 2002; 3(6): 889–901

[98] O’Conor CJ, Griffin TM, Liedtke W, Guilak F. Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis 2013; 72(2): 300–304

[99] Masuyama R, Mizuno A, Komori H, Kajiya H, Uekawa A, Kitaura H, Okabe K, Ohyama K, Komori T. Calcium/calmodulin-signaling supports TRPV4 activation in osteoclasts and regulates bone mass. J Bone Miner Res 2012; 27(8): 1708–1721

[100] Lee KL, Guevarra MD, Nguyen AM, Chua MC, Wang Y, Jacobs CR. The primary cilium functions as a mechanical and calcium signaling nexus. Cilia 2015; 4(1): 7

[101] Phan MN, Leddy HA, Votta BJ, Kumar S, Levy DS, Lipshutz DB, Lee SH, Liedtke W, Guilak F. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum 2009; 60(10): 3028–3037

[102] Han SJ, Kim JI, Park KM. P26 Hydrogen sulfide elongates primary cilia in the kidney tubular epithelial cells. Nitric Oxide 2014; 39(Supplement): S24

[103] Miyoshi K, Kasahara K, Miyazaki I, Asanuma M. Factors that influence primary cilium length. Acta Med Okayama 2011; 65(5): 279–285

[104] Xiao ZS, Quarles LD. Role of the polycytin-primary cilia complex in bone development and mechanosensing. Ann N Y Acad Sci 2010; 1192(1): 410–421

[105] Li Q, Montalbetti N, Wu Y, Ramos A, Raychowdhury MK, Chen XZ, Cantiello HF. Polycystin-2 cation channel function is under the control of microtubular structures in primary cilia of renal epithelial cells. J Biol Chem 2006; 281(49): 37566–37575

[106] Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003; 33(2): 129–137

[107] Spasic M, Jacobs CR. Primary cilia: cell and molecular mechanosensors directing whole tissue function. Semin Cell Dev Biol 2017; 71: 42–52

[108] Qiu N, Cao L, David V, Quarles LD, Xiao Z. Kif3a deficiency reverses the skeletal abnormalities in Pkd1 deficient mice by restoring the balance between osteogenesis and adipogenesis. PLoS One 2010; 5(12): e15240

[109] Jin X, Mohieldin AM, Muntean BS, Green JA, Shah JV, Mykytyn K, Nauli SM. Cilioplasm is a cellular compartment for calcium signaling in response to mechanical and chemical stimuli. Cell Mol Life Sci 2014; 71(11): 2165–2178

[110] Saunders MM, You J, Zhou Z, Li Z, Yellowley CE, Kunze EL, Jacobs CR, Donahue HJ. Fluid flow-induced prostaglandin E2 response of osteoblastic ROS 17/2.8 cells is gap junction-mediated and independent of cytosolic calcium. Bone 2003; 32(4): 350–356

[111] Jing D, Shen G, Huang J, Xie K, Cai J, Xu Q, Wu X, Luo E. Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. Bone 2010; 46(2): 487–495

[112] Garland DE, Adkins RH, Matsuno NN, Stewart CA. The effect of pulsed electromagnetic fields on osteoporosis at the knee in individuals with spinal cord injury. J Spinal Cord Med 1999; 22(4): 239–245

[113] Tabrah FL, Ross P, Hoffmeier M, Gilbert F Jr. Clinical report on long-term bone density after short-term EMF application. Bioelectromagnetics 1998; 19(2): 75–78

[114] Funk RH, Monsees T, Ozkucur N. Electromagnetic effects—from cell biology to medicine. Prog Histochem Cytochem 2009; 43(4): 177–264

[115] Yan JL, Zhou J, Ma HP, Ma XN, Gao YH, Shi WG, Fang QQ, Ren Q, Xian CJ, Chen KM. Pulsed electromagnetic fields promote osteoblast mineralization and maturation needing the existence of primary cilia. Mol Cell Endocrinol 2015; 404: 132–140

[116] Wang YY, Pu XY, Shi WG, Fang QQ, Chen XR, Xi HR, Gao YH, Zhou J, Xian CJ, Chen KM. Pulsed electromagnetic fields promote bone formation by activating the sAC-cAMP-PKA-CREB signaling pathway. J Cell Physiol 2019; 234(3): 2807–2821

[117] Shi W, Gao Y, Wang Y, Zhou J, Wei Z, Ma X, Ma H, Xian CJ, Wang J, Chen K. The flavonol glycoside icariin promotes bone formation in growing rats by activating the cAMP signaling pathway in primary cilia of osteoblasts. J Biol Chem 2017; 292(51): 20883–20896

[118] Zhou J, Gao YH, Zhu BY, Shao JL, Ma HP, Xian CJ, Chen KM. Sinusoidal electromagnetic fields increase peak bone mass in rats by activating Wnt10b/-catenin in primary cilia of osteoblasts. J Bone Miner Res 2019; 34(7): 1336–1351

[119] McCullen SD, McQuilling JP, Grossfeld RM, Lubischer JL, Clarke LI, Loboa EG. Application of low-frequency alternating current electric fields via interdigitated electrodes: effects on cellular viability, cytoplasmic calcium, and osteogenic differentiation of human adipose-derived stem cells. Tissue Eng Part C Methods 2010; 16(6): 1377–1386

[120] Sun S, Liu Y, Lipsky S, Cho M. Physical manipulation of calcium oscillations facilitates osteodifferentiation of human mesenchymal stem cells. FASEB J 2007; 21(7): 1472–1480

[121] Khatib L, Golan DE, Cho M. Physiologic electrical stimulation provokes intracellular calcium increase mediated by phospholipase C activation in human osteoblasts. FASEB J 2004; 18(15): 1903–1905

[122] Zhang J, Li M, Kang ET, Neoh KG. Electrical stimulation of adipose-derived mesenchymal stem cells in conductive scaffolds and the roles of voltage-gated ion channels. Acta Biomater 2016; 32: 46–56

[123] Xu J, Wang W, Clark CC, Brighton CT. Signal transduction in electrically stimulated articular chondrocytes involves translocation of extracellular calcium through voltage-gated channels. Osteoarthritis Cartilage 2009; 17(3): 397–405

[124] Bergh JJ, Xu Y, Farach-Carson MC. Osteoprotegerin expression and secretion are regulated by calcium influx through the L-type voltage-sensitive calcium channel. Endocrinology 2004; 145(1): 426–436

[125] Reiter JF, Leroux MR. Genes and molecular pathways underpinning ciliopathies. Nat Rev Mol Cell Biol 2017; 18(9): 533–547

[126] Novarino G, Akizu N, Gleeson JG. Modeling human disease in humans: the ciliopathies. Cell 2011; 147(1): 70–79

[127] Wheway G, Parry DA, Johnson CA. The role of primary cilia in the development and disease of the retina. Organogenesis 2014; 10(1): 69–85

[128] Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol 2011; 26(7): 1039–1056

[129] Perrault I, Saunier S, Hanein S, Filhol E, Bizet AA, Collins F, Salih MA, Gerber S, Delphin N, Bigot K, Orssaud C, Silva E, Baudouin V, Oud MM, Shannon N, Le Merrer M, Roche O, Pietrement C, Goumid J, Baumann C, Bole-Feysot C, Nitschke P, Zahrate M, Beales P, Arts HH, Munnich A, Kaplan J, Antignac C, Cormier-Daire V, Rozet JM. Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations. Am J Hum Genet 2012; 90(5): 864–870

[130] Rix S, Calmont A, Scambler PJ, Beales PL. An Ift80 mouse model of short rib polydactyly syndromes shows defects in hedgehog signalling without loss or malformation of cilia. Hum Mol Genet 2011; 20(7): 1306–1314

[131] Dagoneau N, Goulet M, Geneviève D, Sznajer Y, Martinovic J, Smithson S, Huber C, Baujat G, Flori E, Tecco L, Cavalcanti D, Delezoide AL, Serre V, Le Merrer M, Munnich A, Cormier-Daire V. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet 2009; 84(5): 706–711

[132] Saldino RM, Noonan CD. Severe thoracic dystrophy with striking micromelia, abnormal osseous development, including the spine, and multiple visceral anomalies. Am J Roentgenol Radium Ther Nucl Med 1972; 114(2): 257–263

[133] Yang SS, Roth JA, Langer LO Jr. Short rib syndrome Beemer-Langer type with polydactyly: a multiple congenital anomalies syndrome. Am J Med Genet 1991; 39(3): 243–246

[134] Elçioglu NH, Hall CM. Diagnostic dilemmas in the short rib-polydactyly syndrome group. Am J Med Genet 2002; 111(4): 392–400

[135] Majewski F, Pfeiffer RA, Lenz W, Müller R, Feil G, Seiler R. Polysyndactyly, short limbs, and genital malformations—a new syndrome? Z Kinderheilkd 1971; 111(2): 118–138 (in German)

[136] Naumoff P, Young LW, Mazer J, Amortegui AJ. Short rib-polydactyly syndrome type 3. Radiology 1977; 122(2): 443–447

[137] Meizner I, Barnhard Y. Short-rib polydactyly syndrome (SRPS) type III diagnosed during routine prenatal ultrasonographic screening. A case report. Prenat Diagn 1995; 15(7): 665–668

[138] Cideciyan D, Rodriguez MM, Haun RL, Abdenour GE, Bruce JH. New findings in short rib syndrome. Am J Med Genet 1993; 46(3): 255–259

[139] Schmidts M, Arts HH, Bongers EMHF, Yap Z, Oud MM, Antony D, Duijkers L, Emes RD, Stalker J, Yntema JBL, Plagnol V, Hoischen A, Gilissen C, Forsythe E, Lausch E, Veltman JA, Roeleveld N, Superti-Furga A, Kutkowska-Kazmierczak A, Kamsteeg EJ, Elçioğlu N, van Maarle MC, Graul-Neumann LM, Devriendt K, Smithson SF, Wellesley D, Verbeek NE, Hennekam RCM, Kayserili H, Scambler PJ, Beales PL; UK10K, Knoers NV, Roepman R, Mitchison HM. Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement. J Med Genet 2013; 50(5): 309–323

[140] Baujat G, Huber C, El Hokayem J, Caumes R, Do Ngoc Thanh C, David A, Delezoide AL, Dieux-Coeslier A, Estournet B, Francannet C, Kayirangwa H, Lacaille F, Le Bourgeois M, Martinovic J, Salomon R, Sigaudy S, Malan V, Munnich A, Le Merrer M, Le Quan Sang KH, Cormier-Daire V. Asphyxiating thoracic dysplasia: clinical and molecular review of 39 families. J Med Genet 2013; 50(2): 91–98

[141] Schmidts M, Frank V, Eisenberger T, Al Turki S, Bizet AA, Antony D, Rix S, Decker C, Bachmann N, Bald M, Vinke T, Toenshoff B, Di Donato N, Neuhann T, Hartley JL, Maher ER, Bogdanović R, Peco-Antić A, Mache C, Hurles ME, Joksić I, Guć-Šćekić M, Dobricic J, Brankovic-Magic M, Bolz HJ, Pazour GJ, Beales PL, Scambler PJ, Saunier S, Mitchison HM, Bergmann C. Combined NGS approaches identify mutations in the intraflagellar transport gene IFT140 in skeletal ciliopathies with early progressive kidney disease. Hum Mutat 2013; 34(5): 714–724

[142] Tüysüz B, Bariş S, Aksoy F, Madazli R, Ungür S, Sever L. Clinical variability of asphyxiating thoracic dystrophy (Jeune) syndrome: Evaluation and classification of 13 patients. Am J Med Genet A 2009; 149A(8): 1727–1733

[143] Jonassen JA, SanAgustin J, Baker SP, Pazour GJ. Disruption of IFT complex A causes cystic kidneys without mitotic spindle misorientation. J Am Soc Nephrol 2012; 23(4): 641–651

[144] Schmidts M, Vodopiutz J, Christou-Savina S, Cortés CR, McInerney-Leo AM, Emes RD, Arts HH, Tüysüz B, D’Silva J, Leo PJ, Giles TC, Oud MM, Harris JA, Koopmans M, Marshall M, Elçioglu N, Kuechler A, Bockenhauer D, Moore AT, Wilson LC, Janecke AR, Hurles ME, Emmet W, Gardiner B, Streubel B, Dopita B, Zankl A, Kayserili H, Scambler PJ, Brown MA, Beales PL, Wicking C; UK10K, Duncan EL, Mitchison HM. Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy. Am J Hum Genet 2013; 93(5): 932–944

[145] Oberklaid F, Danks DM, Mayne V, Campbell P. Asphyxiating thoracic dysplasia. Clinical, radiological, and pathological information on 10 patients. Arch Dis Child 1977; 52(10): 758–765

[146] Beals RK, Weleber RG. Conorenal dysplasia: a syndrome of cone-shaped epiphysis, renal disease in childhood, retinitis pigmentosa and abnormality of the proximal femur. Am J Med Genet A 2007; 143A(20): 2444–2447

[147] Eke T, Woodruff G, Young ID. A new oculorenal syndrome: retinal dystrophy and tubulointerstitial nephropathy in cranioectodermal dysplasia. Br J Ophthalmol 1996; 80(5): 490–491

[148] Walczak-Sztulpa J, Eggenschwiler J, Osborn D, Brown DA, Emma F, Klingenberg C, Hennekam RC, Torre G, Garshasbi M, Tzschach A, Szczepanska M, Krawczynski M, Zachwieja J, Zwolinska D, Beales PL, Ropers HH, Latos-Bielenska A, Kuss AW. Cranioectodermal dysplasia, Sensenbrenner syndrome, is a ciliopathy caused by mutations in the IFT122 gene. Am J Hum Genet 2010; 86(6): 949–956

[149] Bredrup C, Saunier S, Oud MM, Fiskerstrand T, Hoischen A, Brackman D, Leh SM, Midtbø M, Filhol E, Bole-Feysot C, Nitschké P, Gilissen C, Haugen OH, Sanders JS, Stolte-Dijkstra I, Mans DA, Steenbergen EJ, Hamel BC, Matignon M, Pfundt R, Jeanpierre C, Boman H, Rødahl E, Veltman JA, Knappskog PM, Knoers NV, Roepman R, Arts HH. Ciliopathies with skeletal anomalies and renal insufficiency due to mutations in the IFT-A gene WDR19. Am J Hum Genet 2011; 89(5): 634–643

[150] Lee E, Sivan-Loukianova E, Eberl DF, Kernan MJ. An IFT-A protein is required to delimit functionally distinct zones in mechanosensory cilia. Curr Biol 2008; 18(24): 1899–1906

[151] Merrill AE, Merriman B, Farrington-Rock C, Camacho N, Sebald ET, Funari VA, Schibler MJ, Firestein MH, Cohn ZA, Priore MA, Thompson AK, Rimoin DL, Nelson SF, Cohn DH, Krakow D. Ciliary abnormalities due to defects in the retrograde transport protein DYNC2H1 in short-rib polydactyly syndrome. Am J Hum Genet 2009; 84(4): 542–549

[152] Porter ME, Bower R, Knott JA, Byrd P, Dentler W. Cytoplasmic dynein heavy chain 1b is required for flagellar assembly in Chlamydomonas. Mol Biol Cell 1999; 10(3): 693–712

[153] Miller KA, Ah-Cann CJ, Welfare MF, Tan TY, Pope K, Caruana G, Freckmann ML, Savarirayan R, Bertram JF, Dobbie MS, Bateman JF, Farlie PG. Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling Jeune syndrome. PLoS Genet 2013; 9(8): e1003746

[154] Beales PL, Bland E, Tobin JL, Bacchelli C, Tuysuz B, Hill J, Rix S, Pearson CG, Kai M, Hartley J, Johnson C, Irving M, Elcioglu N, Winey M, Tada M, Scambler PJ. IFT80, which encodes a conserved intraflagellar transport protein, is mutated in Jeune asphyxiating thoracic dystrophy. Nat Genet 2007; 39(6): 727–729

[155] Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV, Muzny DM, Young AC, Wheeler DA, Cruz P, Morgan M, Lewis LR, Cherukuri P, Maskeri B, Hansen NF, Mullikin JC, Blakesley RW, Bouffard GG; NISC Comparative Sequencing Program, Gyapay G, Rieger S, Tönshoff B, Kern I, Soliman NA, Neuhaus TJ, Swoboda KJ, Kayserili H, Gallagher TE, Lewis RA, Bergmann C, Otto EA, Saunier S, Scambler PJ, Beales PL, Gleeson JG, Maher ER, Attié-Bitach T, Dollfus H, Johnson CA, Green ED, Gibbs RA, Hildebrandt F, Pierce EA, Katsanis N, Katsanis N. TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 2011; 43(3): 189–196

[156] Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA, Gee HY, McInerney-Leo AM, Krug P, Filhol E, Davis EE, Airik R, Czarnecki PG, Lehman AM, Trnka P, Nitschké P, Bole-Feysot C, Schueler M, Knebelmann B, Burtey S, Szabó AJ, Tory K, Leo PJ, Gardiner B, McKenzie FA, Zankl A, Brown MA, Hartley JL, Maher ER, Li C, Leroux MR, Scambler PJ, Zhan SH, Jones SJ, Kayserili H, Tuysuz B, Moorani KN, Constantinescu A, Krantz ID, Kaplan BS, Shah JV; UK10K Consortium,Hurd TW, Doherty D, Katsanis N, Duncan EL, Otto EA, Beales PL, Mitchison HM, Saunier S, Hildebrandt F. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet 2013; 93(5): 915–925

[157] Tao D, Xue H, Zhang C, Li G, Sun Y. The role of IFT140 in osteogenesis of adult mice long bone. J Histochem Cytochem 2019; 67(8): 601–611

[158] Gao D, Wang R, Li B, Yang Y, Zhai Z, Chen DY. WDR34 is a novel TAK1-associated suppressor of the IL-1R/TLR3/TLR4-induced NF-κB activation pathway. Cell Mol Life Sci 2009; 66(15): 2573–2584

[159] Krock BL, Mills-Henry I, Perkins BD. Retrograde intraflagellar transport by cytoplasmic dynein-2 is required for outer segment extension in vertebrate photoreceptors but not arrestin translocation. Invest Ophthalmol Vis Sci 2009; 50(11): 5463–5471

[160] Ruiz-Perez VL, Blair HJ, Rodriguez-Andres ME, Blanco MJ, Wilson A, Liu YN, Miles C, Peters H, Goodship JA. Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development 2007; 134(16): 2903–2912

[161] Caparrós-Martín JA, Valencia M, Reytor E, Pacheco M, Fernandez M, Perez-Aytes A, Gean E, Lapunzina P, Peters H, Goodship JA, Ruiz-Perez VL. The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Hum Mol Genet 2013; 22(1): 124–139

[162] Martik ML, Bronner ME. Regulatory logic underlying diversification of the neural crest. Trends Genet 2017; 33(10): 715–727

[163] Cortés CR, Metzis V, Wicking C. Unmasking the ciliopathies: craniofacial defects and the primary cilium. Wiley Interdiscip Rev Dev Biol 2015; 4(6): 637–653

[164] Wang SF, Kowal TJ, Ning K, Koo EB, Wu AY, Mahajan VB, Sun Y. Review of ocular manifestations of Joubert syndrome. Genes (Basel) 2018; 9(12): 605

[165] Molinari E, Ramsbottom SA, Srivastava S, Booth P, Alkanderi S, McLafferty SM, Devlin LA, White K, Gunay-Aygun M, Miles CG, Sayer JA. Targeted exon skipping rescues ciliary protein composition defects in Joubert syndrome patient fibroblasts. Sci Rep 2019; 9(1): 10828

[166] Del Giudice E, Macca M, Imperati F, D’Amico A, Parent P, Pasquier L, Layet V, Lyonnet S, Stamboul-Darmency V, Thauvin-Robinet C, Franco B; Oral-Facial-Digital Type I (OFD1) Collaborative Group. CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging study. Orphanet J Rare Dis 2014; 9(1): 74

[167] Singla V, Romaguera-Ros M, Garcia-Verdugo JM, Reiter JF. Ofd1, a human disease gene, regulates the length and distal structure of centrioles. Dev Cell 2010; 18(3): 410–424

[168] Ferrante MI, Giorgio G, Feather SA, Bulfone A, Wright V, Ghiani M, Selicorni A, Gammaro L, Scolari F, Woolf AS, Sylvie O, Bernard L, Malcolm S, Winter R, Ballabio A, Franco B. Identification of the gene for oral-facial-digital type I syndrome. Am J Hum Genet 2001; 68(3): 569–576

[169] AlKattan WM, Al-Qattan MM, Bafaqeeh SA. The pathogenesis of the clinical features of oral-facial-digital syndrome type I. Saudi Med J 2015; 36(11): 1277–1284

[170] Ferrante MI, Zullo A, Barra A, Bimonte S, Messaddeq N, Studer M, Dollé P, Franco B. Oral-facial-digital type I protein is required for primary cilia formation and left-right axis specification. Nat Genet 2006; 38(1): 112–117

[171] Romani M, Mancini F, Micalizzi A, Poretti A, Miccinilli E, Accorsi P, Avola E, Bertini E, Borgatti R, Romaniello R, Ceylaner S, Coppola G, D’Arrigo S, Giordano L, Janecke AR, Lituania M, Ludwig K, Martorell L, Mazza T, Odent S, Pinelli L, Poo P, Santucci M, Signorini S, Simonati A, Spiegel R, Stanzial F, Steinlin M, Tabarki B, Wolf NI, Zibordi F, Boltshauser E, Valente EM. Oral-facial-digital syndrome type VI: is C5orf42 really the major gene? Hum Genet 2015; 134(1): 123–126

[172] Poretti A, Vitiello G, Hennekam RC, Arrigoni F, Bertini E, Borgatti R, Brancati F, D’Arrigo S, Faravelli F, Giordano L, Huisman TA, Iannicelli M, Kluger G, Kyllerman M, Landgren M, Lees MM, Pinelli L, Romaniello R, Scheer I, Schwarz CE, Spiegel R, Tibussek D, Valente EM, Boltshauser E. Delineation and diagnostic criteria of oral-facial-digital syndrome type VI. Orphanet J Rare Dis 2012; 7(1): 4

[173] Asadollahi R, Strauss JE, Zenker M, Beuing O, Edvardson S, Elpeleg O, Strom TM, Joset P, Niedrist D, Otte C, Oneda B, Boonsawat P, Azzarello-Burri S, Bartholdi D, Papik M, Zweier M, Haas C, Ekici AB, Baumer A, Boltshauser E, Steindl K, Nothnagel M, Schinzel A, Stoeckli ET, Rauch A. Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling. Eur J Hum Genet 2018; 26(2): 197–209

[174] Tobin JL, Di Franco M, Eichers E, May-Simera H, Garcia M, Yan J, Quinlan R, Justice MJ, Hennekam RC, Briscoe J, Tada M, Mayor R, Burns AJ, Lupski JR, Hammond P, Beales PL. Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung’s disease in Bardet–Biedl syndrome. Proc Natl Acad Sci U S A 2008; 105(18): 6714–6719

[175] Borgström MK, Riise R, Tornqvist K, Granath L. Anomalies in the permanent dentition and other oral findings in 29 individuals with Laurence–Moon–Bardet–Biedl syndrome. J Oral Pathol Med 1996; 25(2): 86–89

[176] Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet–Biedl syndrome: results of a population survey. J Med Genet 1999; 36(6): 437–446

[177] Andersson EM, Axelsson S, Gjølstad LF, Storhaug K. Taurodontism: a minor diagnostic criterion in Laurence–Moon/Bardet–Biedl syndromes. Acta Odontol Scand 2013; 71(6): 1671–1674

[178] Heon E, Kim G, Qin S, Garrison JE, Tavares E, Vincent A, Nuangchamnong N, Scott CA, Slusarski DC, Sheffield VC. Mutations in C8ORF37 cause Bardet Biedl syndrome (BBS21). Hum Mol Genet 2016; 25(11): 2283–2294

[179] Ludlam WG, Aoba T, Cuéllar J, Bueno-Carrasco MT, Makaju A, Moody JD, Franklin S, Valpuesta JM, Willardson BM. Molecular architecture of the Bardet-Biedl syndrome protein 2-7-9 subcomplex. J Biol Chem 2019; 294(44): 16385–16399

[180] Tayeh MK, Yen HJ, Beck JS, Searby CC, Westfall TA, Griesbach H, Sheffield VC, Slusarski DC. Genetic interaction between Bardet–Biedl syndrome genes and implications for limb patterning. Hum Mol Genet 2008; 17(13): 1956–1967

[181] Zhang Q, Seo S, Bugge K, Stone EM, Sheffield VC. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes. Hum Mol Genet 2012; 21(9): 1945–1953

[182] Valencia M, Lapunzina P, Lim D, Zannolli R, Bartholdi D, Wollnik B, Al-Ajlouni O, Eid SS, Cox H, Buoni S, Hayek J, Martinez-Frias ML, Antonio PA, Temtamy S, Aglan M, Goodship JA, Ruiz-Perez VL. Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling. Hum Mutat 2009; 30(12): 1667–1675

[183] Shen W, Han D, Zhang J, Zhao H, Feng H. Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family. Am J Med Genet Part A 2011; 155 (9): 2131–2136

[184] Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, King L, Francomano C, Freisinger P, Spranger S, Marino B, Dallapiccola B, Wright M, Meitinger T, Polymeropoulos MH, Goodship J. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet 2000; 24(3): 283–286

[185] Baujat G, Le Merrer M. Ellis-van Creveld syndrome. Orphanet J Rare Dis 2007; 2(1): 27

[186] Hampl M, Cela P, Szabo-Rogers HL, Kunova Bosakova M, Dosedelova H, Krejci P, Buchtova M. Role of primary cilia in odontogenesis. J Dent Res 2017; 96(9): 965–974

[187] Nakatomi M, Hovorakova M, Gritli-Linde A, Blair HJ, MacArthur K, Peterka M, Lesot H, Peterkova R, Ruiz-Perez VL, Goodship JA, Peters H. Evc regulates a symmetrical response to Shh signaling in molar development. J Dent Res 2013; 92(3): 222–228

[188] Curry CJ, Hall BD. Polydactyly, conical teeth, nail dysplasia, and short limbs: a new autosomal dominant malformation syndrome. Birth Defects Orig Artic Ser 1979; 15(5B): 253–263

[189] Roubicek M, Spranger J. Weyers acrodental dysostosis in a family. Clin Genet 1984; 26(6): 587–590

[190] Ye X, Song G, Fan M, Shi L, Jabs EW, Huang S, Guo R, Bian Z. A novel heterozygous deletion in the EVC2 gene causes Weyers acrofacial dysostosis. Hum Genet 2006; 119(1-2): 199–205

[191] Veis A. Mineral-matrix interactions in bone and dentin. J Bone Miner Res 1993; 8(Suppl 2): S493–S497

[192] Hisamoto M, Goto M, Muto M, Nio-Kobayashi J, Iwanaga T, Yokoyama A. Developmental changes in primary cilia in the mouse tooth germ and oral cavity. Biomed Res 2016; 37(3): 207–214

[193] Kero D, Novakovic J, Vukojevic K, Petricevic J, Kalibovic Govorko D, Biocina-Lukenda D, Saraga-Babic M. Expression of Ki-67, Oct-4, g-tubulin and α-tubulin in human tooth development. Arch Oral Biol 2014; 59(11): 1119–1129

[194] Jung SY, Green DW, Jung HS, Kim EJ. Cell cycle of the enamel knot during tooth morphogenesis. Histochem Cell Biol 2018; 149(6): 655–659

[195] Jernvall J, Kettunen P, Karavanova I, Martin LB, Thesleff I. Evidence for the role of the enamel knot as a control center in mammalian tooth cusp formation: non-dividing cells express growth stimulating Fgf-4 gene. Int J Dev Biol 1994; 38(3): 463–469

[196] Thivichon-Prince B, Couble ML, Giamarchi A, Delmas P, Franco B, Romio L, Struys T, Lambrichts I, Ressnikoff D, Magloire H, Bleicher F. Primary cilia of odontoblasts: possible role in molar morphogenesis. J Dent Res 2009; 88(10): 910–915

[197] Yuan X, Liu M, Cao X, Yang S. Ciliary IFT80 regulates dental pulp stem cells differentiation by FGF/FGFR1 and Hh/BMP2 signaling. Int J Biol Sci 2019; 15(10): 2087–2099

[198] Dassule HR, Lewis P, Bei M, Maas R, McMahon AP. Sonic hedgehog regulates growth and morphogenesis of the tooth. Development 2000; 127(22): 4775–4785

[199] Ohazama A, Haycraft CJ, Seppala M, Blackburn J, Ghafoor S, Cobourne M, Martinelli DC, Fan CM, Peterkova R, Lesot H, Yoder BK, Sharpe PT. Primary cilia regulate Shh activity in the control of molar tooth number. Development 2009; 136(6): 897–903

[200] Liu B, Chen S, Cheng D, Jing W, Helms JA. Primary cilia integrate hedgehog and Wnt signaling during tooth development. J Dent Res 2014; 93(5): 475–482

[201] Li G, Liu M, Zhang S, Wan H, Zhang Q, Yue R, Yan X, Wang X, Wang Z, Sun Y. Essential role of IFT140 in promoting dentinogenesis. J Dent Res 2018; 97(4): 423–431

[202] Li X, Yang S, Han L, Mao K, Yang S. Ciliary IFT80 is essential for intervertebral disc development and maintenance. FASEB J 2020; 34(5): 6741–6756

[203] Kitamura A, Kawasaki M, Kawasaki K, Meguro F, Yamada A, Nagai T, Kodama Y, Trakanant S, Sharpe PT, Maeda T, Takagi R, Ohazama A. Ift88 is involved in mandibular development. J Anat 2020; 236(2): 317–324

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82061130222, 81822012, 81771043, 92049201, 81770873, and 81802193), the National Science and Technology Major Project of China (No. 2016YFC-1102705), the Shanghai Academic Leader of Science and Technology Innovation Action Plan (No. 20XD1424000), and the Shanghai Experimental Animal Research Project of Science and Technology Innovation Action Plan (No. 8191101676). We also apologize to the many researchers whose work could not be cited due to the limited scope of discussion in this evolving field.

Compliance with ethics guidelines

Sijin Li, Han Zhang, and Yao Sun declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by a relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2021 Higher Education Press