{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T18:25:47Z","timestamp":1767896747415,"version":"3.49.0"},"reference-count":111,"publisher":"SAGE Publications","issue":"4","license":[{"start":{"date-parts":[[2004,7,1]],"date-time":"2004-07-01T00:00:00Z","timestamp":1088640000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Critical Reviews in Oral Biology &amp; Medicine"],"published-print":{"date-parts":[[2004,7]]},"abstract":"<jats:p> The bilaterally symmetric body plan of vertebrates features several consistent asymmetries in the placement, structure, and function of organs such as the heart, intestine, and brain. Deviations from the normal pattern result in situs inversus, isomerisms, or heterotaxia (independent randomization), which have significant clinical implications. The invariance of the left-right (LR) asymmetry of normal morphology, neuronal function, and phenotype of several syndromes raises fascinating and fundamental questions in cell, developmental, evolutionary, and neurobiology. While a pathway of asymmetrically expressed signaling factors has been well-characterized in several model systems, very early steps in the establishment of LR asymmetry remain poorly understood. In particular, the origin of consistently oriented asymmetry is unknown. Recently, a candidate for the origins of asymmetry has been suggested: bulk transport of extracellular morphogens by rotating primary cilia during gastrulation. This model is appealing because it \u2018bootstraps\u2019 morphological asymmetry of the embryo from the intrinsic structural (molecular) chirality of motile cilia. However, conceptual and practical problems remain with this hypothesis. Indeed, the genetic data are also consistent with a different mechanism: cytoplasmic transport roles of motor proteins. This review outlines the progress and remaining questions in the field of left-right asymmetry, and focuses on an alternative model for \u2018Step 1\u2019 of asymmetry. More specifically, based on wide-ranging data on ion fluxes and motor protein function in several species, it is suggested that laterality is driven by pH\/voltage gradients across the midline, which are established by chiral movement of motor proteins with respect to the cytoskeleton. <\/jats:p>","DOI":"10.1177\/154411130401500403","type":"journal-article","created":{"date-parts":[[2009,1,9]],"date-time":"2009-01-09T00:40:32Z","timestamp":1231461632000},"page":"197-206","source":"Crossref","is-referenced-by-count":66,"title":["T<scp>he<\/scp> E<scp>mbryonic<\/scp> O<scp>rigins of<\/scp> L<scp>eft-<\/scp>R<scp>ight<\/scp> A<scp>symmetry<\/scp>"],"prefix":"10.1177","volume":"15","author":[{"given":"Michael","family":"Levin","sequence":"first","affiliation":[{"name":"Cytokine Biology Dept., The Forsyth Institute, and Department of Craniofacial and Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"179","published-online":{"date-parts":[[2004,7,1]]},"reference":[{"key":"ABYHOLM-1978","doi-asserted-by":"publisher","DOI":"10.3109\/02844317809010477"},{"key":"AFZELIUS-1976","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084576"},{"key":"ALBRIEUX-AND-VILLAZ-2000","doi-asserted-by":"publisher","DOI":"10.1016\/S0248-4900(00)01066-2"},{"key":"ANSLEY-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1038\/nature02030"},{"key":"ANTCZAK-AND-VAN-BLERKOM-1997","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/3.12.1067"},{"key":"BARISONI-ETAL-1995","unstructured":"Barisoni L, Trudel M, Chretien N, Ward L, Van Adelsberg J, D\u2019Agati V (1995). Analysis of the role of membrane polarity in polycystic kidney disease of transgenic SBM mice. Am J Pathol 147:1728\u20131735."},{"key":"BRIZUELA-ETAL-2001","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.0116"},{"key":"BROWN-AND-WOLPERT-1990","doi-asserted-by":"crossref","unstructured":"Brown N, Wolpert L (1990). The development of handedness in left\/right asymmetry. Development 109:1\u20139.","DOI":"10.1242\/dev.109.1.1"},{"key":"BUNNEY-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00698"},{"key":"BURDINE-AND-SCHIER-2000","doi-asserted-by":"crossref","unstructured":"Burdine R, Schier A (2000). Conserved and divergent mechanisms in left-right axis formation. Genes Dev 14:763\u2013776.","DOI":"10.1101\/gad.14.7.763"},{"key":"BURN-1991","doi-asserted-by":"crossref","unstructured":"Burn J (1991). Disturbance of morphological laterality in humans. CIBA Found Symp 162:282\u2013296.","DOI":"10.1002\/9780470514160.ch16"},{"key":"CASEY-AND-HACKETT-2000","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(00)00085-X"},{"key":"CHANG-ETAL-1960","unstructured":"Chang KS, Hsu FK, Chan ST, Chan YB (1960). Scrotal asymmetry and handedness. J Anat 94:543\u2013548."},{"key":"CHENEVIX-TRENCH-ETAL-1992","unstructured":"Chenevix-Trench G, Jones K, Green AC, Duffy DL, Martin NG (1992). Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci [comment]. Am J Hum Genet 51:1377\u20131385."},{"key":"COCKAYNE-1938","unstructured":"Cockayne E (1938). The genetics of transposition of the viscera. Q J Med 31:479\u2013493."},{"key":"DANE-ETAL-2001","doi-asserted-by":"publisher","DOI":"10.2466\/pms.2001.93.2.329"},{"key":"DANE-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.2466\/pms.2002.95.2.416"},{"key":"DANOS-AND-YOST-1995","doi-asserted-by":"crossref","unstructured":"Danos MC, Yost HJ (1995). Linkage of cardiac left-right asymmetry and dorsal-anterior development in Xenopus. Development 121(Suppl):1467\u20131474.","DOI":"10.1242\/dev.121.5.1467"},{"key":"ESSNER-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1038\/418037a"},{"key":"FARMER-1972","doi-asserted-by":"publisher","DOI":"10.1007\/BF00401394"},{"key":"FREEMAN-AND-LUNDELIUS-1982","doi-asserted-by":"publisher","DOI":"10.1007\/BF00848443"},{"key":"FUJINAGA-AND-BADEN-1991","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(91)90067-D"},{"key":"GARDNER-2001","doi-asserted-by":"crossref","unstructured":"Gardner RL (2001). Specification of embryonic axes begins before cleavage in normal mouse development. Development 128(Suppl):839\u2013847.","DOI":"10.1242\/dev.128.6.839"},{"key":"GILLESPIE-ETAL-1991","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.10.4289"},{"key":"GINKEL-AND-WORDEMAN-2000","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.11.12.4143"},{"key":"GOLBIN-ETAL-1993","doi-asserted-by":"publisher","DOI":"10.1017\/S0001566000003238"},{"key":"GONZALEZ-PERRETT-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M105084200"},{"key":"HAMM-ALVAREZ-AND-SHEETZ-1998","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1998.78.4.1109"},{"key":"HANAOKA-ETAL-2000","doi-asserted-by":"publisher","DOI":"10.1038\/35050128"},{"key":"HAPPLE-ETAL-1995","doi-asserted-by":"publisher","DOI":"10.1159\/000246548"},{"key":"HARAGSIM-ETAL-1995","unstructured":"Haragsim L, Rankin C, Bastani B (1995). H-ATPase distribution in the cpk- and ppcy- mouse models of polycystic kidney disease (PKD) (abstract). J Am Soc Nephrol 6:375."},{"key":"HARNAD-1977","unstructured":"Harnad S (1977). Lateralization in the nervous system. New York: Academic Press."},{"key":"HOBERT-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1038\/nrn897"},{"key":"HOLDER-ETAL-1992","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.6.390"},{"key":"HOLT-1968","unstructured":"Holt SB (1968). The genetics of dermal ridges. Springfield, IL: Charles C. Thomas."},{"key":"HYATT-AND-YOST-1998","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81144-7"},{"key":"JANUSCHKE-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01302-7"},{"key":"KANDL-ETAL-1995","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.6.11.1549"},{"key":"KENNEDY-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.53.6.1260"},{"key":"KIMURA-AND-CARSON-1995","doi-asserted-by":"crossref","unstructured":"Kimura D, Carson MW (1995). Dermatoglyphic asymmetry: relation to sex, handedness and cognitive pattern. Personality Individ Diff 4:471\u2013478.","DOI":"10.1016\/0191-8869(95)00076-I"},{"key":"KOULEN-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1038\/ncb754"},{"key":"KRAMER-AND-YOST-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00107-1"},{"key":"KRAMER-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)01200-X"},{"key":"LE-BOT-ETAL-1998","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.143.6.1559"},{"key":"LEVIN-1997","doi-asserted-by":"publisher","DOI":"10.1002\/bies.950190406"},{"key":"LEVIN-1998","doi-asserted-by":"publisher","DOI":"10.1006\/scdb.1997.0192"},{"key":"LEVIN-1999","doi-asserted-by":"publisher","DOI":"10.1080\/713754338"},{"key":"LEVIN-2003A","doi-asserted-by":"publisher","DOI":"10.1002\/bem.10104"},{"key":"LEVIN-2003B","unstructured":"Levin M (2003b). Electric embryos: endogenous ion fluxes and voltage gradients in left-right asymmetry (abstract). Dev Biol 259:482."},{"key":"LEVIN-AND-MERCOLA-1998","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1998.9024"},{"key":"LEVIN-AND-MERCOLA-1999","doi-asserted-by":"crossref","unstructured":"Levin M, Mercola M (1999). Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node. Development 126:4703\u20134714.","DOI":"10.1242\/dev.126.21.4703"},{"key":"LEVIN-AND-NASCONE-1997","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-9877(97)90092-X"},{"key":"LEVIN-ETAL-1995","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90477-8"},{"key":"LEVIN-ETAL-1996","doi-asserted-by":"publisher","DOI":"10.1038\/384321a0"},{"key":"LEVIN-ETAL-1997","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1997.8662"},{"key":"LEVIN-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00939-X"},{"key":"LEVY-AND-LEVY-1978","doi-asserted-by":"publisher","DOI":"10.1126\/science.663611"},{"key":"LINASK-ETAL-2001","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.1131"},{"key":"LIPTAU-AND-VIEBAHN-1999","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-0436.1999.6540209.x"},{"key":"LOWE-ETAL-1996","doi-asserted-by":"publisher","DOI":"10.1038\/381158a0"},{"key":"MARSZALEK-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.9.5043"},{"key":"MCGRATH-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00511-7"},{"key":"MCMANUS-1991","doi-asserted-by":"crossref","unstructured":"McManus IC (1991). The inheritance of left-handedness. Ciba Found Symp 162:251\u2013281.","DOI":"10.1002\/9780470514160.ch15"},{"key":"MCMANUS-2002","unstructured":"McManus IC (2002). Right hand, left hand: the origins of asymmetry in brains, bodies, atoms and cultures. London: Weidenfeld and Nicolson."},{"key":"MCMANUS-ETAL","unstructured":"McManus IC, Martin N, Stubbings G, Chung EMK, Mitchison HM (in press). Handedness and situs inversus in primary ciliary dyskinesia."},{"key":"MERCOLA-AND-LEVIN-2001","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.17.1.779"},{"key":"MITTWOCH-2000","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3075"},{"key":"MITTWOCH-2001","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1091"},{"key":"NEVILLE-1976","unstructured":"Neville A (1976). Animal asymmetry. London: Edward Arnold."},{"key":"NONAKA-ETAL-1998","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81705-5"},{"key":"NONAKA-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1038\/nature00849"},{"key":"OGBORN-ETAL-1995","doi-asserted-by":"publisher","DOI":"10.1177\/43.8.7622841"},{"key":"OLBRICH-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1038\/ng817"},{"key":"PAGAN-WESTPHAL-AND-TABIN-1998","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81143-5"},{"key":"PASTEUR-1860","unstructured":"Pasteur L (1860). Researches on molecular asymmetry. Alembic Club Reprint Vol. 14."},{"key":"PAULI-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(98)00231-0"},{"key":"PAZOUR-AND-WITMAN-2003","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(02)00012-1"},{"key":"PAZOUR-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.144.3.473"},{"key":"PAZOUR-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00877-1"},{"key":"PENNEKAMP-ETAL-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00869-2"},{"key":"PIEDRA-ETAL-1998","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81475-0"},{"key":"PIOTROWSKA-AND-ZERNICKA-GOETZ-2001","doi-asserted-by":"publisher","DOI":"10.1038\/35054069"},{"key":"PSYCHOYOS-AND-STERN-1996","doi-asserted-by":"crossref","unstructured":"Psychoyos D, Stern C (1996). Restoration of the organizer after radical ablation of Hensen\u2019s node and the anterior primitive streak in the chick embryo. Development 122:3263\u20133273.","DOI":"10.1242\/dev.122.10.3263"},{"key":"ROBINSON-AND-MESSERLI-1996","unstructured":"Robinson K, Messerli M (1996). Electric embryos: the embryonic epithelium as a generator of developmental information. In: Nerve growth and guidance. McCaig C, editor. Portland: Portland Press, pp. 131\u2013141."},{"key":"ROBINSON-AND-MESSERLI-2003","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10307"},{"key":"ROOKLIN-ETAL-1980","doi-asserted-by":"crossref","unstructured":"Rooklin AR, McGeady SJ, Mikaelian DO, Soriano RZ, Mansmann HC Jr (1980). The immotile cilia syndrome: a cause of recurrent pulmonary diseases in children. Pediatrics 66:526\u2013531.","DOI":"10.1542\/peds.66.4.526"},{"key":"SANDSON-ETAL-1992","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)90341-Y"},{"key":"SEDAR-1956","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1401330103"},{"key":"SNYDER-AND-HARRIS-1997","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3932(97)00010-9"},{"key":"STERN-ETAL-1995","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1995.0015"},{"key":"SULIK-ETAL-1994","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1002010309"},{"key":"SUPP-ETAL-1997","doi-asserted-by":"publisher","DOI":"10.1038\/40140"},{"key":"SUPP-ETAL-1999","doi-asserted-by":"crossref","unstructured":"Supp DM, Brueckner M, Kuehn MR, Witte DP, Lowe LA, McGrath J, et al. (1999). Targeted deletion of the ATP binding domain of left-right dynein confirms its role in specifying development of left-right asymmetries. Development 126(Suppl):5495\u20135504.","DOI":"10.1242\/dev.126.23.5495"},{"key":"TABIN-AND-VOGAN-2003","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1053803"},{"key":"TAKEDA-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.145.4.825"},{"key":"TAMM-AND-TERASAKI-1994","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.125.5.1127"},{"key":"TAMURA-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-169X.1999.00465.x"},{"key":"TANAKA-ETAL-1999","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3932(98)00144-4"},{"key":"TEKOTTE-AND-DAVIS-2002","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(02)02819-6"},{"key":"TORGERSEN-1950","unstructured":"Torgersen J (1950). Situs inversus, asymmetry and twinning. Am J Hum Genet 2:361\u2013370."},{"key":"TOYOIZUMI-ETAL-1997","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-169X.1997.t01-3-00012.x"},{"key":"VAISBERG-ETAL-1996","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.133.4.831"},{"key":"VALE-1999","doi-asserted-by":"publisher","DOI":"10.1016\/S0962-8924(99)01665-7"},{"key":"VAN-NIEKERK-AND-RETIEF-1981","doi-asserted-by":"publisher","DOI":"10.1007\/BF00284158"},{"key":"WAGNER-AND-YOST-2000","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)00312-2"},{"key":"WATANABE-ETAL-2003","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00407"},{"key":"WENTZLAFF-ETAL-1997","unstructured":"Wentzlaff KA, Cooper ME, Yang P, Aston CP, Liu YE, Melnick M, et al. (1997). Association between non-right-handedness and cleft lip with or without cleft palate in a Chinese population. J Craniofac Genet Dev Biol 17:141\u2013147."},{"key":"WILSON-ETAL-2000","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64726-8"},{"key":"WOOD-1991","doi-asserted-by":"publisher","DOI":"10.1038\/349536a0"},{"key":"WOOD-1997","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.13.1.53"},{"key":"YOST-1990","doi-asserted-by":"crossref","unstructured":"Yost HJ (1990). Development of the left-right axis amphibians. Ciba Found Symp 162:165\u2013176.","DOI":"10.1002\/9780470514160.ch10"}],"container-title":["Critical Reviews in Oral Biology &amp; Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/154411130401500403","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/154411130401500403","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/154411130401500403","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,5]],"date-time":"2024-10-05T16:41:51Z","timestamp":1728146511000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/154411130401500403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,7]]},"references-count":111,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2004,7]]}},"alternative-id":["10.1177\/154411130401500403"],"URL":"https:\/\/doi.org\/10.1177\/154411130401500403","relation":{},"ISSN":["1045-4411","1544-1113"],"issn-type":[{"value":"1045-4411","type":"print"},{"value":"1544-1113","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,7]]}}}