231
Formation of the Left-Right Axis
Grimes, D.T., Burdine, R.D., 2017. Left-right patterning: breaking
symmetry to asymmetric morphogenesis. Trends in genetics : TIG. https://doi.org/10.1016/j.tig.2017.06.004
Hamada, H., Meno, C., Watanabe, D., Saijoh, Y., 2002.
Establishment of vertebrate left-right asymmetry. Nature
Reviews Genetics 3, 103–113. https://doi.org/10.1038/nrg732
Hirokawa, N., Tanaka, Y., Okada, Y., 2012. Cilia, KIF3 molecular
motor and nodal f ow. Current Opinion in Cell Biology 24,
31–39. https://doi.org/10.1016/j.ceb.2012.01.002
Hojo, M., Takashima, S., Kobayashi, D., Sumeragi, A., Shimada,
A., Tsukahara, T., Yokoi, H., Narita, T., Jindo, T., Kage,
T., Kitagawa, T., Kimura, T., Sekimizu, K., Miyake, A.,
Setiamarga, D., Murakami, R., Tsuda, S., Ooki, S., Kakihara,
K., Naruse, K., Takeda, H., 2007. Right-elevated expression
of charon is regulated by f uid fow in medaka Kupffer’s vesicle. Development Growth and Differentiation 49, 395–405.
https://doi.org/10.1111/j.1440-169x.2007.00937.x
Kajikawa, E., Horo, U., Ide, T., Mizuno, K., Minegishi, K., Hara,
Y., Ikawa, Y., Nishimura, H., Uchikawa, M., Kiyonari, H.,
Kuraku, S., Hamada, H., 2020. Nodal paralogues underlie
distinct mechanisms for visceral left-right asymmetry in reptiles and mammals. Nature Ecology & Evolution 4, 261–269.
https://doi.org/10.1038/s41559-019-1072-2
Kamura, K., Kobayashi, D., Uehara, Y., Koshida, S., Iijima, N.,
Kudo, A., Yokoyama, T., Takeda, H., 2011. Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish
the left-right axis. Development (Cambridge, England) 138,
1121–1129. https://doi.org/10.1242/dev.058271
Little, R.B., Norris, D.P., 2020. Right, left and cilia: How asymmetry is established. Semin Cell Dev Biol. https://doi.
org/10.1016/j.semcdb.2020.06.003
Maerker, M., Getwan, M., Dowdle, M.E., Pelliccia, J.L.,
McSheene, J.C., Yartseva, V., Minegishi, K., Vick, P.,
Giraldez, A.J., Hamada, H., Burdine, R.D., Sheets, M.D.,
Schweickert, A., Blum, M., 2020. Bicc1 and dicer regulate
left-right patterning through post-transcriptional control of
the Nodal-inhibitor dand5. Biorxiv 1(29), 924456. https://
doi.org/10.1101/2020.01.29.924456
Maisonneuve, C., Guilleret, I., Vick, P., Weber, T., Andre, P., Beyer,
T., Blum, M., Constam, D.B., 2009. Bicaudal C, a novel
regulator of Dvl signaling abutting RNA-processing bodies,
controls cilia orientation and leftward f ow. Development
(Cambridge, England) 136, 3019–3030. https://doi.org/10.
1242/dev.038174
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. https://doi.org/10.1016/
s0092-8674(03)00511-7
Moody, S.A., 1987. Fates of the blastomeres of the 32-cell-stage
Xenopus embryo. Dev Biol 122, 300–319. https://doi.
org/10.1016/0012-1606(87)90296-x
Nakamura, T., Saito, D., Kawasumi, A., Shinohara, K., Asai,
Y., Takaoka, K., Dong, F., Takamatsu, A., Belo, J.-A.,
Mochizuki, A., Hamada, H., 2012. Fluid fow and interlinked
feedback loops establish left-right asymmetric decay of
Cerl2 mRNA. Nature communications 3, 1322. https://doi.
org/10.1038/ncomms2319
Rothé, B., Leal-Esteban, L., Bernet, F., Urfer, S., Doerr, N.,
Weimbs, T., Iwaszkiewicz, J., Constam, D.B., 2015. Bicc1
polymerization regulates the localization and silencing of
bound mRNA. Mol Cell Biol 35, 3339–3353. https://doi.
org/10.1128/mcb.00341-15
Schweickert, A., Vick, P., Getwan, M., Weber, T., Schneider, I.,
Eberhardt, M., Beyer, T., Pachur, A., Blum, M., 2010. The
nodal inhibitor Coco is a critical target of leftward f ow in
Xenopus. Current Biology: CB 20, 738–743. https://doi.
org/10.1016/j.cub.2010.02.061
Schweickert, A., Weber, T., Beyer, T., Vick, P., Bogusch, S., Feistel,
K., Blum, M., 2007. Cilia-driven leftward f ow determines
laterality in Xenopus. Current Biology: CB 17, 60–66.
https://doi.org/10.1016/j.cub.2006.10.067
Shinohara, K., Hamada, H., 2017. Cilia in left-right symmetry
breaking. Cold Spring Harbor Perspectives in Biology.
https://doi.org/10.1101/cshperspect.a028282
Shiratori, H., Hamada, H., 2014. TGF signaling in establishing
left-right asymmetry. Semin Cell Dev Biol 32, 80–84. https://
doi.org/10.1016/j.semcdb.2014.03.029
Shook, D.R., Majer, C., Keller, R., 2004. Pattern and morphogenesis of presumptive superfcial mesoderm in two
closely related species, Xenopus laevis and Xenopus tropicalis. Developmental Biology 270, 163–185. https://doi.
org/10.1016/j.ydbio.2004.02.021
Tabin, C.J., Vogan, K.J., 2003. A two-cilia model for vertebrate
left-right axis specif cation. Genes and Development 17, 1–6.
https://doi.org/10.1101/gad.1053803
Tanaka, Y., Okada, Y., Hirokawa, N., 2005. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward
nodal fow is critical for left-right determination. Nature 435,
172–177. https://doi.org/10.1038/nature03494
Tisler, M., Schweickert, A., Blum, M., 2017a. Xenopus, an ideal
model organism to study laterality in conjoined twins.
Genesis (New York, NY : 2000) 55. https://doi.org/10.1002/
dvg.22993
Tisler, M., Thumberger, T., Schneider, I., Schweickert, A., Blum,
M., 2017b. Leftward fow determines laterality in conjoined twins. Current Biology: CB 27, 543–548. https://doi.
org/10.1016/j.cub.2016.12.049
Tran, U., Zakin, L., Schweickert, A., Agrawal, R., Döger, R.,
Blum, M., Robertis, E.M.D., Wessely, O., 2010. The
RNA-binding protein bicaudal C regulates polycystin 2 in
the kidney by antagonizing miR-17 activity. Development
(Cambridge, England) 137, 1107–1116. https://doi.org/10.
1242/dev.046045
Vetrini, F., D’Alessandro, L.C.A., Akdemir, Z.C., Braxton, A.,
Azamian, M.S., Eldomery, M.K., Miller, K., Kois, C.,
Sack, V., Shur, N., Rijhsinghani, A., Chandarana, J., Ding,
Y., Holtzman, J., Jhangiani, S.N., Muzny, D.M., Gibbs,
R.A., Eng, C.M., Hanchard, N.A., Harel, T., Rosenfeld,
J.A., Belmont, J.W., Lupski, J.R., Yang, Y., 2016. Bi-allelic
mutations in PKD1L1 are associated with laterality defects
in humans. Am J Hum Genetics 99, 886–893. https://doi.
org/10.1016/j.ajhg.2016.07.011
Vick, P., Schweickert, A., Weber, T., Eberhardt, M., Mencl, S.,
Shcherbakov, D., Beyer, T., Blum, M., 2009. Flow on the
right side of the gastrocoel roof plate is dispensable for symmetry breakage in the frog Xenopus laevis. Dev Biol 331,
281–291. https://doi.org/10.1016/j.ydbio.2009.05.547
Vonica, A., Brivanlou, A.H., 2007. The left-right axis is regulated
by the interplay of Coco, Xnr1 and derrière in Xenopus
embryos. Developmental Biology 303, 281–294. https://doi.
org/10.1016/j.ydbio.2006.09.039
Wallmeier, J., Nielsen, K.G., Kuehni, C.E., Lucas, J.S., Leigh,
M.W., Zariwala, M.A., Omran, H., 2020. Motile ciliopathies. Nature Reviews: Disease Primers 6, 77–29. https://doi.
org/10.1038/s41572-020-0209-6
Yoshiba, S., Hamada, H., 2014. Roles of cilia, f uid fow, and Ca2+
signaling in breaking of left-right symmetry. Trends Genet
30, 10–17. https://doi.org/10.1016/j.tig.2013.09.001
Formation of the Left-Right Axis
Grimes, D.T., Burdine, R.D., 2017. Left-right patterning: breaking
symmetry to asymmetric morphogenesis. Trends in genetics : TIG. https://doi.org/10.1016/j.tig.2017.06.004
Hamada, H., Meno, C., Watanabe, D., Saijoh, Y., 2002.
Establishment of vertebrate left-right asymmetry. Nature
Reviews Genetics 3, 103–113. https://doi.org/10.1038/nrg732
Hirokawa, N., Tanaka, Y., Okada, Y., 2012. Cilia, KIF3 molecular
motor and nodal f ow. Current Opinion in Cell Biology 24,
31–39. https://doi.org/10.1016/j.ceb.2012.01.002
Hojo, M., Takashima, S., Kobayashi, D., Sumeragi, A., Shimada,
A., Tsukahara, T., Yokoi, H., Narita, T., Jindo, T., Kage,
T., Kitagawa, T., Kimura, T., Sekimizu, K., Miyake, A.,
Setiamarga, D., Murakami, R., Tsuda, S., Ooki, S., Kakihara,
K., Naruse, K., Takeda, H., 2007. Right-elevated expression
of charon is regulated by f uid fow in medaka Kupffer’s vesicle. Development Growth and Differentiation 49, 395–405.
https://doi.org/10.1111/j.1440-169x.2007.00937.x
Kajikawa, E., Horo, U., Ide, T., Mizuno, K., Minegishi, K., Hara,
Y., Ikawa, Y., Nishimura, H., Uchikawa, M., Kiyonari, H.,
Kuraku, S., Hamada, H., 2020. Nodal paralogues underlie
distinct mechanisms for visceral left-right asymmetry in reptiles and mammals. Nature Ecology & Evolution 4, 261–269.
https://doi.org/10.1038/s41559-019-1072-2
Kamura, K., Kobayashi, D., Uehara, Y., Koshida, S., Iijima, N.,
Kudo, A., Yokoyama, T., Takeda, H., 2011. Pkd1l1 complexes with Pkd2 on motile cilia and functions to establish
the left-right axis. Development (Cambridge, England) 138,
1121–1129. https://doi.org/10.1242/dev.058271
Little, R.B., Norris, D.P., 2020. Right, left and cilia: How asymmetry is established. Semin Cell Dev Biol. https://doi.
org/10.1016/j.semcdb.2020.06.003
Maerker, M., Getwan, M., Dowdle, M.E., Pelliccia, J.L.,
McSheene, J.C., Yartseva, V., Minegishi, K., Vick, P.,
Giraldez, A.J., Hamada, H., Burdine, R.D., Sheets, M.D.,
Schweickert, A., Blum, M., 2020. Bicc1 and dicer regulate
left-right patterning through post-transcriptional control of
the Nodal-inhibitor dand5. Biorxiv 1(29), 924456. https://
doi.org/10.1101/2020.01.29.924456
Maisonneuve, C., Guilleret, I., Vick, P., Weber, T., Andre, P., Beyer,
T., Blum, M., Constam, D.B., 2009. Bicaudal C, a novel
regulator of Dvl signaling abutting RNA-processing bodies,
controls cilia orientation and leftward f ow. Development
(Cambridge, England) 136, 3019–3030. https://doi.org/10.
1242/dev.038174
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. https://doi.org/10.1016/
s0092-8674(03)00511-7
Moody, S.A., 1987. Fates of the blastomeres of the 32-cell-stage
Xenopus embryo. Dev Biol 122, 300–319. https://doi.
org/10.1016/0012-1606(87)90296-x
Nakamura, T., Saito, D., Kawasumi, A., Shinohara, K., Asai,
Y., Takaoka, K., Dong, F., Takamatsu, A., Belo, J.-A.,
Mochizuki, A., Hamada, H., 2012. Fluid fow and interlinked
feedback loops establish left-right asymmetric decay of
Cerl2 mRNA. Nature communications 3, 1322. https://doi.
org/10.1038/ncomms2319
Rothé, B., Leal-Esteban, L., Bernet, F., Urfer, S., Doerr, N.,
Weimbs, T., Iwaszkiewicz, J., Constam, D.B., 2015. Bicc1
polymerization regulates the localization and silencing of
bound mRNA. Mol Cell Biol 35, 3339–3353. https://doi.
org/10.1128/mcb.00341-15
Schweickert, A., Vick, P., Getwan, M., Weber, T., Schneider, I.,
Eberhardt, M., Beyer, T., Pachur, A., Blum, M., 2010. The
nodal inhibitor Coco is a critical target of leftward f ow in
Xenopus. Current Biology: CB 20, 738–743. https://doi.
org/10.1016/j.cub.2010.02.061
Schweickert, A., Weber, T., Beyer, T., Vick, P., Bogusch, S., Feistel,
K., Blum, M., 2007. Cilia-driven leftward f ow determines
laterality in Xenopus. Current Biology: CB 17, 60–66.
https://doi.org/10.1016/j.cub.2006.10.067
Shinohara, K., Hamada, H., 2017. Cilia in left-right symmetry
breaking. Cold Spring Harbor Perspectives in Biology.
https://doi.org/10.1101/cshperspect.a028282
Shiratori, H., Hamada, H., 2014. TGF signaling in establishing
left-right asymmetry. Semin Cell Dev Biol 32, 80–84. https://
doi.org/10.1016/j.semcdb.2014.03.029
Shook, D.R., Majer, C., Keller, R., 2004. Pattern and morphogenesis of presumptive superfcial mesoderm in two
closely related species, Xenopus laevis and Xenopus tropicalis. Developmental Biology 270, 163–185. https://doi.
org/10.1016/j.ydbio.2004.02.021
Tabin, C.J., Vogan, K.J., 2003. A two-cilia model for vertebrate
left-right axis specif cation. Genes and Development 17, 1–6.
https://doi.org/10.1101/gad.1053803
Tanaka, Y., Okada, Y., Hirokawa, N., 2005. FGF-induced vesicular release of Sonic hedgehog and retinoic acid in leftward
nodal fow is critical for left-right determination. Nature 435,
172–177. https://doi.org/10.1038/nature03494
Tisler, M., Schweickert, A., Blum, M., 2017a. Xenopus, an ideal
model organism to study laterality in conjoined twins.
Genesis (New York, NY : 2000) 55. https://doi.org/10.1002/
dvg.22993
Tisler, M., Thumberger, T., Schneider, I., Schweickert, A., Blum,
M., 2017b. Leftward fow determines laterality in conjoined twins. Current Biology: CB 27, 543–548. https://doi.
org/10.1016/j.cub.2016.12.049
Tran, U., Zakin, L., Schweickert, A., Agrawal, R., Döger, R.,
Blum, M., Robertis, E.M.D., Wessely, O., 2010. The
RNA-binding protein bicaudal C regulates polycystin 2 in
the kidney by antagonizing miR-17 activity. Development
(Cambridge, England) 137, 1107–1116. https://doi.org/10.
1242/dev.046045
Vetrini, F., D’Alessandro, L.C.A., Akdemir, Z.C., Braxton, A.,
Azamian, M.S., Eldomery, M.K., Miller, K., Kois, C.,
Sack, V., Shur, N., Rijhsinghani, A., Chandarana, J., Ding,
Y., Holtzman, J., Jhangiani, S.N., Muzny, D.M., Gibbs,
R.A., Eng, C.M., Hanchard, N.A., Harel, T., Rosenfeld,
J.A., Belmont, J.W., Lupski, J.R., Yang, Y., 2016. Bi-allelic
mutations in PKD1L1 are associated with laterality defects
in humans. Am J Hum Genetics 99, 886–893. https://doi.
org/10.1016/j.ajhg.2016.07.011
Vick, P., Schweickert, A., Weber, T., Eberhardt, M., Mencl, S.,
Shcherbakov, D., Beyer, T., Blum, M., 2009. Flow on the
right side of the gastrocoel roof plate is dispensable for symmetry breakage in the frog Xenopus laevis. Dev Biol 331,
281–291. https://doi.org/10.1016/j.ydbio.2009.05.547
Vonica, A., Brivanlou, A.H., 2007. The left-right axis is regulated
by the interplay of Coco, Xnr1 and derrière in Xenopus
embryos. Developmental Biology 303, 281–294. https://doi.
org/10.1016/j.ydbio.2006.09.039
Wallmeier, J., Nielsen, K.G., Kuehni, C.E., Lucas, J.S., Leigh,
M.W., Zariwala, M.A., Omran, H., 2020. Motile ciliopathies. Nature Reviews: Disease Primers 6, 77–29. https://doi.
org/10.1038/s41572-020-0209-6
Yoshiba, S., Hamada, H., 2014. Roles of cilia, f uid fow, and Ca2+
signaling in breaking of left-right symmetry. Trends Genet
30, 10–17. https://doi.org/10.1016/j.tig.2013.09.001