Abstract
Mutation of ZIC3 causes X-linked heterotaxy, a syndrome in which the laterality of internal organs is disrupted. Analysis of model organisms and gene expression during early development suggests ZIC3-related heterotaxy occurs due to defects at the earliest stage of left-right axis formation. Although there are data to support abnormalities of the node and cilia as underlying causes, it is unclear at the molecular level why loss of ZIC3 function causes such these defects. ZIC3 has putative roles in a number of developmental signalling pathways that have distinct roles in establishing the left-right axis. This complicates the understanding of the mechanistic basis of Zic3 in early development and left-right patterning. Here we summarise our current understanding of ZIC3 function and describe the potential role ZIC3 plays in important signalling pathways and their links to heterotaxy.
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References
Ahmed JN et al (2013) A murine Zic3 transcript with a premature termination codon evades nonsense-mediated decay during axis formation. Dis Model Mech 6:755–767. https://doi.org/10.1242/dmm.011668
Allache R et al (2014) Novel mutations in Lrp6 orthologs in mouse and human neural tube defects affect a highly dosage-sensitive Wnt non-canonical planar cell polarity pathway. Hum Mol Genet 23:1687–1699. https://doi.org/10.1093/hmg/ddt558
Antic D, Stubbs JL, Suyama K, Kintner C, Scott MP, Axelrod JD (2010) Planar cell polarity enables posterior localization of nodal cilia and left-right axis determination during mouse and Xenopus embryogenesis. PLoS One 5:e8999. https://doi.org/10.1371/journal.pone.0008999
Aruga J et al (2006) A wide-range phylogenetic analysis of Zic proteins: implications for correlations between protein structure conservation and body plan complexity. Genomics 87:783–792. https://doi.org/10.1016/j.ygeno.2006.02.011
Axelrod JD (2001) Unipolar membrane association of dishevelled mediates frizzled planar cell polarity signaling. Genes Dev 15:1182–1187. https://doi.org/10.1101/gad.890501
Babu D, Roy S (2013) Left-right asymmetry: cilia stir up new surprises in the node. Open Biol 3:130052. https://doi.org/10.1098/rsob.130052
Badis G et al (2009) Diversity and complexity in DNA recognition by transcription factors. Science (New York, NY) 324:1720–1723. https://doi.org/10.1126/science.1162327
Bamford RN et al (2000) Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26:365–369. https://doi.org/10.1038/81695
Bangs F, Anderson KV (2017) Primary Cilia and Mammalian Hedgehog Signaling. Cold Spring Harb Perspect Biol 9. https://doi.org/10.1101/cshperspect.a028175
Bastock R, Strutt H, Strutt D (2003) Strabismus is asymmetrically localised and binds to prickle and dishevelled during drosophila planar polarity patterning. Development (Cambridge, UK) 130:3007–3014
Bedard JE, Purnell JD, Ware SM (2007) Nuclear import and export signals are essential for proper cellular trafficking and function of ZIC3. Hum Mol Genet 16:187–198. https://doi.org/10.1093/hmg/ddl461
Bedard JE, Haaning AM, Ware SM (2011) Identification of a novel ZIC3 isoform and mutation screening in patients with heterotaxy and congenital heart disease. PLoS One 6:e23755. https://doi.org/10.1371/journal.pone.0023755
Bitgood MJ, Shen L, McMahon AP (1996) Sertoli cell signaling by desert hedgehog regulates the male germline. Curr Biol 6:298–304
Blank MC, Grinberg I, Aryee E, Laliberte C, Chizhikov VV, Henkelman RM, Millen KJ (2011) Multiple developmental programs are altered by loss of Zic1 and Zic4 to cause Dandy-Walker malformation cerebellar pathogenesis. Development (Cambridge, UK) 138:1207–1216. https://doi.org/10.1242/dev.054114
Blum M, Feistel K, Thumberger T, Schweickert A (2014) The evolution and conservation of left-right patterning mechanisms. Development (Cambridge, UK) 141:1603–1613. https://doi.org/10.1242/dev.100560
Bogani D et al (2004) New semidominant mutations that affect mouse development. Genesis (New York, NY: 2000) 40:109–117. https://doi.org/10.1002/gene.20071
Caron A, Xu X, Lin X (2012) Wnt/beta-catenin signaling directly regulates Foxj1 expression and ciliogenesis in zebrafish Kupffer’s vesicle. Development (Cambridge, UK) 139:514–524. https://doi.org/10.1242/dev.071746
Casey B, Devoto M, Jones KL, Ballabio A (1993) Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27.1. Nat Genet 5:403–407. https://doi.org/10.1038/ng1293-403
Cast AE, Gao C, Amack JD, Ware SM (2012) An essential and highly conserved role for Zic3 in left-right patterning, gastrulation and convergent extension morphogenesis. Dev Biol 364:22–31. https://doi.org/10.1016/j.ydbio.2012.01.011
Chan DW, Liu VW, Leung LY, Yao KM, Chan KK, Cheung AN, Ngan HY (2011) Zic2 synergistically enhances hedgehog signalling through nuclear retention of Gli1 in cervical cancer cells. J Pathol 225:525–534. https://doi.org/10.1002/path.2901
Chen WS et al (2008) Asymmetric homotypic interactions of the atypical cadherin flamingo mediate intercellular polarity signaling. Cell 133:1093–1105. https://doi.org/10.1016/j.cell.2008.04.048
Chen Y, Sasai N, Ma G, Yue T, Jia J, Briscoe J, Jiang J (2011) Sonic hedgehog dependent phosphorylation by CK1alpha and GRK2 is required for ciliary accumulation and activation of smoothened. PLoS Biol 9:e1001083. https://doi.org/10.1371/journal.pbio.1001083
Chhin B et al (2007) Elucidation of penetrance variability of a ZIC3 mutation in a family with complex heart defects and functional analysis of ZIC3 mutations in the first zinc finger domain. Hum Mutat 28:563–570. https://doi.org/10.1002/humu.20480
Chung B, Shaffer LG, Keating S, Johnson J, Casey B, Chitayat D (2011) From VACTERL-H to heterotaxy: variable expressivity of ZIC3-related disorders. Am J Med Genet A 155a:1123–1128. https://doi.org/10.1002/ajmg.a.33859
Correa-Villasenor A, McCarter R, Downing J, Ferencz C (1991) White-black differences in cardiovascular malformations in infancy and socioeconomic factors. The Baltimore-Washington Infant Study Group. Am J Epidemiol 134:393–402
Cowan J, Tariq M, Ware SM (2014) Genetic and functional analyses of ZIC3 variants in congenital heart disease. Hum Mutat 35:66–75. https://doi.org/10.1002/humu.22457
Cowan JR et al (2016) Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects philosophical transactions of the Royal Society of London series B. Biol Sci 371. https://doi.org/10.1098/rstb.2015.0406
D’Alessandro LC, Casey B, Siu VM (2013a) Situs inversus totalis and a novel ZIC3 mutation in a family with X-linked heterotaxy. Congenit Heart Dis 8:E36–E40. https://doi.org/10.1111/j.1747-0803.2011.00602.x
D’Alessandro LC, Latney BC, Paluru PC, Goldmuntz E (2013b) The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle. Am J Med Genet A 161a:792–802. https://doi.org/10.1002/ajmg.a.35849
De Luca A et al (2010) Familial transposition of the great arteries caused by multiple mutations in laterality genes. Heart (British Cardiac Society) 96:673–677. https://doi.org/10.1136/hrt.2009.181685
Dunaeva M, Michelson P, Kogerman P, Toftgard R (2003) Characterization of the physical interaction of Gli proteins with SUFU proteins. J Biol Chem 278:5116–5122. https://doi.org/10.1074/jbc.M209492200
El Malti R et al (2016) A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field. Eur J Hum Genet: EJHG 24:228–236. https://doi.org/10.1038/ejhg.2015.105
Elms P, Scurry A, Davies J, Willoughby C, Hacker T, Bogani D, Arkell R (2004) Overlapping and distinct expression domains of Zic2 and Zic3 during mouse gastrulation. Gene Expr Patterns: GEP 4:505–511. https://doi.org/10.1016/j.modgep.2004.03.003
Fakhro KA et al (2011) Rare copy number variations in congenital heart disease patients identify unique genes in left-right patterning. Proc Natl Acad Sci U S A 108:2915–2920. https://doi.org/10.1073/pnas.1019645108
Feiguin F, Hannus M, Mlodzik M, Eaton S (2001) The ankyrin repeat protein Diego mediates frizzled-dependent planar polarization. Dev Cell 1:93–101
Ferrero GB et al (1997) A submicroscopic deletion in Xq26 associated with familial situs ambiguus. Am J Hum Genet 61:395–401. https://doi.org/10.1086/514857
Field S et al (2011) Pkd1l1 establishes left-right asymmetry and physically interacts with Pkd2. Development (Cambridge, UK) 138:1131–1142. https://doi.org/10.1242/dev.058149
Fritz B et al (2005) Situs ambiguus in a female fetus with balanced (X;21) translocation – evidence for functional nullisomy of the ZIC3 gene? Eur J Hum enet: EJHG 13:34–40. https://doi.org/10.1038/sj.ejhg.5201213
Fujimi TJ, Hatayama M, Aruga J (2012) Xenopus Zic3 controls notochord and organizer development through suppression of the Wnt/beta-catenin signaling pathway. Dev Biol 361:220–231. https://doi.org/10.1016/j.ydbio.2011.10.026
Gao B et al (2011) Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2. Dev Cell 20:163–176. https://doi.org/10.1016/j.devcel.2011.01.001
Garnett AT, Square TA, Medeiros DM (2012) BMP, Wnt and FGF signals are integrated through evolutionarily conserved enhancers to achieve robust expression of Pax3 and Zic genes at the zebrafish neural plate border. Development (Cambridge, UK) 139:4220–4231. https://doi.org/10.1242/dev.081497
Gebbia M et al (1997) X-linked situs abnormalities result from mutations in ZIC3. Nat Genet 17:305–308. https://doi.org/10.1038/ng1197-305
Haaning AM, Quinn ME, Ware SM (2013) Heterotaxy-spectrum heart defects in Zic3 hypomorphic mice. Pediatr Res 74:494–502. https://doi.org/10.1038/pr.2013.147
Hamada H, Tam PP (2014) Mechanisms of left-right asymmetry and patterning: driver, mediator and responder. F1000prime Rep 6:110. 10.12703/p6-110
Hashimoto M et al (2010) Planar polarization of node cells determines the rotational axis of node cilia. Nat Cell Biol 12:170–176. https://doi.org/10.1038/ncb2020
Hatayama M et al (2008) Functional and structural basis of the nuclear localization signal in the ZIC3 zinc finger domain. Hum Mol Genet 17:3459–3473. https://doi.org/10.1093/hmg/ddn239
Hierholzer A, Kemler R (2010) Beta-catenin-mediated signaling and cell adhesion in postgastrulation mouse embryos. Dev Dyn: Off Publ Am Assoc Anatomists 239:191–199. https://doi.org/10.1002/dvdy.22075
Houtmeyers R et al (2016) Zic2 mutation causes holoprosencephaly via disruption of NODAL signalling. Hum Mol Genet 25:3946–3959. https://doi.org/10.1093/hmg/ddw235
Huangfu D, Anderson KV (2005) Cilia and hedgehog responsiveness in the mouse. Proc Natl Acad Sci U S A 102:11325–11330. https://doi.org/10.1073/pnas.0505328102
Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426:83–87. https://doi.org/10.1038/nature02061
Humke EW, Dorn KV, Milenkovic L, Scott MP, Rohatgi R (2010) The output of hedgehog signaling is controlled by the dynamic association between suppressor of fused and the Gli proteins. Genes Dev 24:670–682. https://doi.org/10.1101/gad.1902910
Jenny A, Reynolds-Kenneally J, Das G, Burnett M, Mlodzik M (2005) Diego and Prickle regulate frizzled planar cell polarity signalling by competing for dishevelled binding. Nat Cell Biol 7:691–697. https://doi.org/10.1038/ncb1271
Jiang Z, Zhu L, Hu L, Slesnick TC, Pautler RG, Justice MJ, Belmont JW (2013) Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development. Hum Mol Genet 22:879–889. https://doi.org/10.1093/hmg/dds494
Keller MJ, Chitnis AB (2007) Insights into the evolutionary history of the vertebrate zic3 locus from a teleost-specific zic6 gene in the zebrafish, Danio rerio. Dev Genes Evol 217:541–547. https://doi.org/10.1007/s00427-007-0161-4
Kennedy MP et al (2007) Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 115:2814–2821. https://doi.org/10.1161/circulationaha.106.649038
Kim SJ, Kim WH, Lim HG, Lee JY (2008) Outcome of 200 patients after an extracardiac Fontan procedure. J Thorac Cardiovasc Surg 136:108–116. https://doi.org/10.1016/j.jtcvs.2007.12.032
Kitaguchi T, Nagai T, Nakata K, Aruga J, Mikoshiba K (2000) Zic3 is involved in the left-right specification of the Xenopus embryo. Development (Cambridge, UK) 127:4787–4795
Kitajima K, Oki S, Ohkawa Y, Sumi T, Meno C (2013) Wnt signaling regulates left-right axis formation in the node of mouse embryos. Dev Biol 380:222–232. https://doi.org/10.1016/j.ydbio.2013.05.011
Klootwijk R et al (2004) Genetic variants in ZIC1, ZIC2, and ZIC3 are not major risk factors for neural tube defects in humans. Am J Med Genet A 124a:40–47. https://doi.org/10.1002/ajmg.a.20402
Kogerman P et al (1999) Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1:312–319. https://doi.org/10.1038/13031
Koyabu Y, Nakata K, Mizugishi K, Aruga J, Mikoshiba K (2001) Physical and functional interactions between Zic and Gli proteins. J Biol Chem 276:6889–6892. https://doi.org/10.1074/jbc.C000773200
Lee JD, Anderson KV (2008) Morphogenesis of the node and notochord: the cellular basis for the establishment and maintenance of left-right asymmetry in the mouse. Dev Dyn: Off Publ Am Assoc Anatomists 237:3464–3476. https://doi.org/10.1002/dvdy.21598
Lim LS, Hong FH, Kunarso G, Stanton LW (2010) The pluripotency regulator Zic3 is a direct activator of the Nanog promoter in ESCs. Stem Cells (Dayton, Ohio) 28:1961–1969. https://doi.org/10.1002/stem.527
Lin X, Xu X (2009) Distinct functions of Wnt/beta-catenin signaling in KV development and cardiac asymmetry. Development (Cambridge, UK) 136:207–217. https://doi.org/10.1242/dev.029561
Lin AE et al (2014) Laterality defects in the national birth defects prevention study (1998-2007): birth prevalence and descriptive epidemiology. Am J Med Genet A 164a:2581–2591. https://doi.org/10.1002/ajmg.a.36695
Liu C, Lin C, Gao C, May-Simera H, Swaroop A, Li T (2014) Null and hypomorph Prickle1 alleles in mice phenocopy human Robinow syndrome and disrupt signaling downstream of Wnt5a. Biol Open 3:861–870. https://doi.org/10.1242/bio.20148375
Ma L, Selamet Tierney ES, Lee T, Lanzano P, Chung WK (2012) Mutations in ZIC3 and ACVR2B are a common cause of heterotaxy and associated cardiovascular anomalies. Cardiol Young 22:194–201. https://doi.org/10.1017/s1047951111001181
Marques S, Borges AC, Silva AC, Freitas S, Cordenonsi M, Belo JA (2004) The activity of the nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis. Genes Dev 18:2342–2347. https://doi.org/10.1101/gad.306504
Maurus D, Harris WA (2009) Zic-associated holoprosencephaly: zebrafish Zic1 controls midline formation and forebrain patterning by regulating nodal, hedgehog, and retinoic acid signaling. Genes Dev 23:1461–1473. https://doi.org/10.1101/gad.517009
May SR et al (2005) Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287:378–389. https://doi.org/10.1016/j.ydbio.2005.08.050
McGrath J, Somlo S, Makova S, Tian X, Brueckner M (2003) Two populations of node monocilia initiate left-right asymmetry in the mouse. Cell 114:61–73
Megarbane A et al (2000) X-linked transposition of the great arteries and incomplete penetrance among males with a nonsense mutation in ZIC3. Eur J Hum Genet: EJHG 8:704–708. https://doi.org/10.1038/sj.ejhg.5200526
Meyers EN, Martin GR (1999) Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science (New York, NY) 285:403–406
Migeotte I, Grego-Bessa J, Anderson KV (2011) Rac1 mediates morphogenetic responses to intercellular signals in the gastrulating mouse embryo. Development (Cambridge, UK) 138:3011–3020. https://doi.org/10.1242/dev.059766
Milenkovic L, Scott MP, Rohatgi R (2009) Lateral transport of smoothened from the plasma membrane to the membrane of the cilium. J Cell Biol 187:365–374. https://doi.org/10.1083/jcb.200907126
Minegishi K et al (2017) A Wnt5 activity asymmetry and intercellular signaling via PCP proteins polarize node cells for left-right symmetry breaking. Dev Cell 40:439–452.e434. https://doi.org/10.1016/j.devcel.2017.02.010
Mizugishi K, Hatayama M, Tohmonda T, Ogawa M, Inoue T, Mikoshiba K, Aruga J (2004) Myogenic repressor I-mfa interferes with the function of Zic family proteins. Biochem Biophys Res Commun 320:233–240. https://doi.org/10.1016/j.bbrc.2004.05.158
Nagai T, Aruga J, Takada S, Gunther T, Sporle R, Schughart K, Mikoshiba K (1997) The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Dev Biol 182:299–313. https://doi.org/10.1006/dbio.1996.8449
Nakamura T et al (2012) Fluid flow and interlinked feedback loops establish left-right asymmetric decay of Cerl2 mRNA. Nat Commun 3:1322. https://doi.org/10.1038/ncomms2319
Nakaya MA, Biris K, Tsukiyama T, Jaime S, Rawls JA, Yamaguchi TP (2005) Wnt3a links left-right determination with segmentation and anteroposterior axis elongation. Development (Cambridge, UK) 132:5425–5436. https://doi.org/10.1242/dev.02149
Nonaka S, Shiratori H, Saijoh Y, Hamada H (2002) Determination of left-right patterning of the mouse embryo by artificial nodal flow. Nature 418:96–99. https://doi.org/10.1038/nature00849
Nyholm MK, Wu SF, Dorsky RI, Grinblat Y (2007) The zebrafish zic2a-zic5 gene pair acts downstream of canonical Wnt signaling to control cell proliferation in the developing tectum. Development (Cambridge, UK) 134:735–746. https://doi.org/10.1242/dev.02756
Okada Y, Takeda S, Tanaka Y, Izpisua Belmonte JC, Hirokawa N (2005) Mechanism of nodal flow: a conserved symmetry breaking event in left-right axis determination. Cell 121:633–644. https://doi.org/10.1016/j.cell.2005.04.008
Oyen N, Poulsen G, Boyd HA, Wohlfahrt J, Jensen PK, Melbye M (2009) Recurrence of congenital heart defects in families. Circulation 120:295–301. https://doi.org/10.1161/circulationaha.109.857987
Pan H, Gustafsson MK, Aruga J, Tiedken JJ, Chen JC, Emerson CP Jr (2011) A role for Zic1 and Zic2 in Myf5 regulation and somite myogenesis. Dev Biol 351:120–127. https://doi.org/10.1016/j.ydbio.2010.12.037
Parmantier E et al (1999) Schwann cell-derived desert hedgehog controls the development of peripheral nerve sheaths. Neuron 23:713–724
Paulussen AD et al (2016) Rare novel variants in the ZIC3 gene cause X-linked heterotaxy. Eur J Hum Genet: EJHG 24:1783–1791. https://doi.org/10.1038/ejhg.2016.91
Popperl H, Schmidt C, Wilson V, Hume CR, Dodd J, Krumlauf R, Beddington RS (1997) Misexpression of Cwnt8C in the mouse induces an ectopic embryonic axis and causes a truncation of the anterior neuroectoderm. Development (Cambridge, UK) 124:2997–3005
Pourebrahim R et al (2011) Transcription factor Zic2 inhibits Wnt/beta-catenin protein signaling. J Biol Chem 286:37732–37740. https://doi.org/10.1074/jbc.M111.242826
Purandare SM et al (2002) A complex syndrome of left-right axis, central nervous system and axial skeleton defects in Zic3 mutant mice. Development (Cambridge, UK) 129:2293–2302
Quinn ME, Haaning A, Ware SM (2012) Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice. Hum Mol Genet 21:1888–1896. https://doi.org/10.1093/hmg/dds002
Ramalho-Santos M, Melton DA, McMahon AP (2000) Hedgehog signals regulate multiple aspects of gastrointestinal development. Development (Cambridge, UK) 127:2763–2772
Rigler SL et al (2015) Novel copy-number variants in a population-based investigation of classic heterotaxy genetics in medicine: official journal of the American College of Medical. Genetics 17:348–357. https://doi.org/10.1038/gim.2014.112
Rohatgi R, Milenkovic L, Scott MP (2007) Patched1 regulates hedgehog signaling at the primary cilium. Science (New York, NY) 317:372–376. https://doi.org/10.1126/science.1139740
Shapiro AJ et al (2014) Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest 146:1176–1186. https://doi.org/10.1378/chest.13-1704
Shimada Y, Usui T, Yanagawa S, Takeichi M, Uemura T (2001) Asymmetric colocalization of flamingo, a seven-pass transmembrane cadherin, and dishevelled in planar cell polarization. Curr Biol 11:859–863
Song H, Hu J, Chen W, Elliott G, Andre P, Gao B, Yang Y (2010) Planar cell polarity breaks bilateral symmetry by controlling ciliary positioning. Nature 466:378–382. https://doi.org/10.1038/nature09129
St-Jacques B, Hammerschmidt M, McMahon AP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13:2072–2086
Strutt DI (2001) Asymmetric localization of frizzled and the establishment of cell polarity in the drosophila wing. Mol Cell 7:367–375
Sutherland MJ, Ware SM (2009) Disorders of left-right asymmetry: heterotaxy and situs inversus. Am J Med Genet C: Semin Med Genet 151c:307–317. https://doi.org/10.1002/ajmg.c.30228
Sutherland MJ, Wang S, Quinn ME, Haaning A, Ware SM (2013) Zic3 is required in the migrating primitive streak for node morphogenesis and left-right patterning. Hum Mol Genet 22:1913–1923. https://doi.org/10.1093/hmg/ddt001
Tanaka Y, Okada Y, Hirokawa N (2005) FGF-induced vesicular release of sonic hedgehog and retinoic acid in leftward nodal flow is critical for left-right determination. Nature 435:172–177. https://doi.org/10.1038/nature03494
Tree DR, Shulman JM, Rousset R, Scott MP, Gubb D, Axelrod JD (2002) Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 109:371–381
Tsiairis CD, McMahon AP (2009) An Hh-dependent pathway in lateral plate mesoderm enables the generation of left/right asymmetry. Curr Biol 19:1912–1917. https://doi.org/10.1016/j.cub.2009.09.057
Tsukui T et al (1999) Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the shh and retinoic acid pathways in the control of Lefty-1. Proc Natl Acad Sci U S A 96:11376–11381
Tukachinsky H, Lopez LV, Salic A (2010) A mechanism for vertebrate hedgehog signaling: recruitment to cilia and dissociation of SuFu-Gli protein complexes. J Cell Biol 191:415–428. https://doi.org/10.1083/jcb.201004108
Tzschach A et al (2006) Heterotaxy and cardiac defect in a girl with chromosome translocation t(X;1)(q26;p13.1) and involvement of ZIC3. Eur J Hum Genet: EJHG 14:1317–1320. https://doi.org/10.1038/sj.ejhg.5201707
Vierkotten J, Dildrop R, Peters T, Wang B, Ruther U (2007) Ftm is a novel basal body protein of cilia involved in Shh signalling. Development (Cambridge, UK) 134:2569–2577. https://doi.org/10.1242/dev.003715
Wang B, Fallon JF, Beachy PA (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100:423–434
Ware SM et al (2004) Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am J Hum Genet 74:93–105. https://doi.org/10.1086/380998
Ware SM, Harutyunyan KG, Belmont JW (2006a) Heart defects in X-linked heterotaxy: evidence for a genetic interaction of Zic3 with the nodal signaling pathway. Dev Dyn: Off Publ Am Assoc Anatomists 235:1631–1637. https://doi.org/10.1002/dvdy.20719
Ware SM, Harutyunyan KG, Belmont JW (2006b) Zic3 is critical for early embryonic patterning during gastrulation. Dev Dyn: Off Publ Am Assoc Anatomists 235:776–785. https://doi.org/10.1002/dvdy.20668
Weatherbee SD, Niswander LA, Anderson KV (2009) A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and hedgehog signaling. Hum Mol Genet 18:4565–4575. https://doi.org/10.1093/hmg/ddp422
Wessels MW et al (2010) Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? J Med Genet 47:351–355. https://doi.org/10.1136/jmg.2008.060913
Winata CL et al (2013) Genome wide analysis reveals Zic3 interaction with distal regulatory elements of stage specific developmental genes in zebrafish. PLoS Genet 9:e1003852. https://doi.org/10.1371/journal.pgen.1003852
Yoshiba S et al (2012) Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science (New York, NY) 338:226–231. https://doi.org/10.1126/science.1222538
Zeng L et al (1997) The mouse fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90:181–192
Zhang XM, Ramalho-Santos M, McMahon AP (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106:781–792
Zhang M, Zhang J, Lin SC, Meng A (2012) Beta-catenin 1 and beta-catenin 2 play similar and distinct roles in left-right asymmetric development of zebrafish embryos. Development (Cambridge, UK) 139:2009–2019. https://doi.org/10.1242/dev.074435
Zhu L, Harutyunyan KG, Peng JL, Wang J, Schwartz RJ, Belmont JW (2007a) Identification of a novel role of ZIC3 in regulating cardiac development. Hum Mol Genet 16:1649–1660. https://doi.org/10.1093/hmg/ddm106
Zhu L, Peng JL, Harutyunyan KG, Garcia MD, Justice MJ, Belmont JW (2007b) Craniofacial, skeletal, and cardiac defects associated with altered embryonic murine Zic3 expression following targeted insertion of a PGK-NEO cassette. Front Biosci 12:1680–1690
Zhu L, Zhou G, Poole S, Belmont JW (2008) Characterization of the interactions of human ZIC3 mutants with GLI3. Hum Mutat 29:99–105. https://doi.org/10.1002/humu.20606
Zhu P, Xu X, Lin X (2015) Both ciliary and non-ciliary functions of Foxj1a confer Wnt/beta-catenin signaling in zebrafish left-right patterning. Biol Open 4:1376–1386. https://doi.org/10.1242/bio.012088
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Bellchambers, H.M., Ware, S.M. (2018). ZIC3 in Heterotaxy. In: Aruga, J. (eds) Zic family. Advances in Experimental Medicine and Biology, vol 1046. Springer, Singapore. https://doi.org/10.1007/978-981-10-7311-3_15
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DOI: https://doi.org/10.1007/978-981-10-7311-3_15
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