Animals; Animals, Genetically Modified; Body Patterning/genetics; Embryo, Nonmammalian/embryology/metabolism; Forkhead Transcription Factors/genetics/metabolism; Gene Expression; Gene Expression Regulation, Developmental; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism; Mutation/genetics; Nodal Protein; Protein Binding; Signal Transduction/genetics; Transforming Growth Factor beta/metabolism; Zebrafish/embryology/genetics/metabolism; Zebrafish Proteins/deficiency/genetics/metabolism
Abstract :
[en] Remarkable progress has been made in understanding the molecular mechanisms underlying left-right asymmetry in vertebrate animal models but little is known on left-right axis formation in humans. Previously, we identified SESN1 (also known as PA26) as a candidate gene for heterotaxia by positional cloning of the breakpoint regions of a de novo translocation in a heterotaxia patient. In this study, we show by means of a zebrafish sesn1-knockdown model that Sesn1 is required for normal embryonic left-right determination. In this model, developmental defects and expression data of genes implicated in vertebrate left-right asymmetry indicate a role for Sesn1 in mediating Nodal signaling. In the lateral plate mesoderm, Nodal signaling plays a central role in left-right axis formation in vertebrates and is mediated by FoxH1 transcriptional induction. In line with this, we show that Sesn1 physically interacts with FoxH1 or a FoxH1-containing complex. Mutation analysis in a panel of 234 patients with isolated heterotaxia did not reveal mutations, indicating that these are only exceptional causes of human heterotaxia. In this study, we identify SESN1 as an indispensable gene for vertebrate left-right asymmetry and a new player in mediating Nodal signaling.
Research Center/Unit :
Giga-Development and Stem Cells - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Peeters, Hilde; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Human Genetics > Clinical Genetics Unit
Voz, Marianne ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Verschueren, Kristin; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Developmental Biology
De Cat, Bart; University of Leuven > Department of Human Genetics, Molecular Genetics Section > Laboratory of Glycobiology and Developmental Genetics
Pendeville, Helene; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Thienpont, Bernard; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Human Genetics > Clinical Genetics Unit
Schellens, Ann; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Developmental Biology
Belmont, John W; Baylor College of Medicine > Department of Molecular and Human Genetics
David, Guido; University of Leuven > Department of Human Genetics, Molecular Genetics Section > Laboratory of Glycobiology and Developmental Genetics,
Van De Ven, Wim J M; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Human Genetics > Clinical Genetics Unit
Fryns, Jean-Pierre; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Human Genetics > Clinical Genetics Unit
Gewillig, Marc; University of Leuven > Pediatric Cardiology Unit
Huylebroeck, Danny; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Developmental Biology
Peers, Bernard ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Devriendt, Koen; Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology > Department of Human Genetics > Clinical Genetics Unit
Casey, B., Devoto, M., Jones, K.L. and Ballabio, A. (1993) Mapping a gene for familial situs abnormalities to human chromosome Xq24-q27. Nat. Genet., 5, 403-407.
Gebbia, M., Ferrero, G.B., Pilia, G., Bassi, M.T., Aylsworth, A., Penman-Splitt, M., Bird, L.M., Bamforth, J.S., Burn, J., Schlessinger, D. et al. (1997) X-linked situs abnormalities result from mutations in ZIC3. Nat. Genet., 17, 305-308.
Kosaki, R., Gebbia, M., Kosaki, K., Lewin, M., Bowers, P., Towbin, J.A. and Casey, B. (1999) Left-right axis malformations associated with mutations in ACVR2B, the gene for human activin receptor type IIB. Am. J. Med. Genet., 82, 70-76.
Kosaki, K., Bassi, M.T., Kosaki, R., Lewin, M., Belmont, J., Schauer, G. and Casey, B. (1999) Characterization and mutation analysis of human LEFTY A and LEFTY B, homologues of murine genes implicated in left-right axis development. Am. J. Hum. Genet., 64, 712-721.
Bamford, R.N., Roessler, E., Burdine, R.D., Saplakoglu, U., dela Cruz, J., Splitt, M., Goodship, J.A., Towbin, J., Bowers, P., Ferrero, G.B. 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.
Ware, S.M., Peng, J., Zhu, L., Fernbach, S., Colicos, S., Casey, B., Towbin, J. and Belmont, J.W. (2004) Identification and functional analysis of ZIC3 mutations in heterotaxy and related congenital heart defects. Am. J. Hum. Genet., 74, 93-105.
Peeters, H., Debeer, P., Bairoch, A., Wilquet, V., Huysmans, C., Parthoens, E., Fryns, J.P., Gewillig, M., Nakamura, Y., Niikawa, N. et al. (2003) PA26 is a candidate gene for heterotaxia in humans: identification of a novel PA26-related gene family in human and mouse. Hum. Genet., 112, 573-580.
Velasco-Miguel, S., Buckbinder, L., Jean, P., Gelbert, L., Talbott, R., Laidlaw, J., Seizinger, B. and Kley, N. (1999) PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene, 18, 127-137.
Chen, J.N., van Eeden, F.J., Warren, K.S., Chin, A., Nusslein-Volhard, C., Haffter, P. and Fishman, M.C. (1997) Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development, 124, 4373-4382.
Chen, J.N. and Fishman, M.C. (1996) Zebrafish tinman homolog demarcates the heart field and initiates myocardial differentiation. Development, 122, 3809-3816.
Yan, Y.T., Gritsman, K., Ding, J., Burdine, R.D., Corrales, J.D., Price, S.M., Talbot, W.S., Schier, A.F. and Shen, M.M. (1999) Conserved requirement for EGF-CFC genes in vertebrate left-right axis formation. Genes Dev., 13, 2527-2537.
Milewski, W.M., Duguay, S.J., Chan, S.J. and Steiner, D.F. (1998) Conservation of PDX-1 structure, function, and expression in zebrafish. Endocrinology, 139, 1440-1449.
Long, S., Ahmad, N. and Rebagliati, M. (2003) The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development, 130, 2303-2316.
Hamada, H., Meno, C., Watanabe, D. and Saijoh, Y. (2002) Establishment of vertebrate left-right asymmetry. Nat. Rev. Genet., 3, 103-113.
Wright, C.V. (2001) Mechanisms of left-right asymmetry: What's right and what's left? Dev. Cell, 1, 179-186.
Feldman, B., Gates, M.A., Egan, E.S., Dougan, S.T., Rennebeck, G., Sirotkin, H.I., Schier, A.F. and Talbot, W.S. (1998) Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature, 395, 181-185.
Gritsman, K., Zhang, J., Cheng, S., Heckscher, E., Talbot, W.S. and Schier, A.F. (1999) The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell, 97, 121-132.
Sirotkin, H.I., Gates, M.A., Kelly, P.D., Schier, A.F. and Talbot, W.S. (2000) Fast1 is required for the development of dorsal axial structures in zebrafish. Curr. Biol., 10, 1051-1054.
Norris, D.P. and Robertson, E.J. (1999) Asymmetric and node-specific nodal expression patterns are controlled by two distinct cis-acting regulatory elements. Genes. Dev., 13, 1575-1588.
Osada, S.I., Saijoh, Y., Frisch, A., Yeo, C.Y., Adachi, H., Watanabe, M., Whitman, M., Hamada, H. and Wright, C.V. (2000) Activin/nodal responsiveness and asymmetric expression of a Xenopus nodal-related gene converge on a FAST-regulated module in intron 1. Development, 127, 2503-2514.
Pogoda, H.M., Solnica-Krezel, L., Driever, W. and Meyer, D. (2000) The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr. Biol., 10, 1041-1049.
Bisgrove, B.W., Morelli, S.H. and Yost, H.J. (2003) Genetics of human laterality disorders: Insights from vertebrate model systems. Annu. Rev. Genomics Hum. Genet., 4, 1-32.
Capdevila, J., Vogan, K.J., Tabin, C.I. and Izpisua Belmonte, J.C. (2000) Mechanisms of left-right determination in vertebrates. Cell, 101, 9-21.
Mercola, M. and Levin, M. (2001) Left-right asymmetry determination in vertebrates. Annu. Rev. Cell. Dev. Biol., 17, 779-805.
Ramsdell, A.F. and Yost, H.J. (1998) Molecular mechanisms of vertebrate left-right development. Trends Genet., 14, 459-465.
Schier, A.F. and Shen, M.M. (2000) Nodal signalling in vertebrate development. Nature, 403, 385-389.
Bisgrove, B.W., Essner, J.J. and Yost, H.J. (2000) Multiple pathways in the midline regulate concordant brain, heart and gut left-right asymmetry. Development, 127, 3567-3579.
Schier, A.F., Neuhauss, S.C., Helde, K.A., Talbot, W.S. and Driever, W. (1997) The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development, 124, 327-342.
Brand, M., Heisenberg, C.P., Warga, R.M., Pelegri, F., Karlstrom, R.O., Beuchle, D., Picker, A., Jiang, Y.J., Furutani-Seiki, M., van Eeden, F.J. et al. (1996) Mutations affecting development of the midline and general body shape during zebrafish embryogenesis. Development, 123, 129-142.
Solnica-Krezel, L., Stemple, D.L., Mountcastle-Shah, E., Rangini, Z., Neuhauss, S.C., Malicki, J., Schier, A.F., Stainier, D.Y., Zwartkruis, F., Abdelilah, S. et al. (1996) Mutations affecting cell fates and cellular rearrangements during gastrulation in zebrafish. Development, 123, 67-80.
Budanov, A.V., Sablina, A.A., Feinstein, E., Koonin, E.V. and Chumakov, P.M. (2004) Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD. Science, 304, 596-600.
Jowett, T. (2001) Double in situ hybridization techniques in zebrafish. Methods, 23, 345-358.
Collart, C., Remacle, J.E., Barabino, S., van Grunsven, L.A., Nelles, L., Schellens, A., Van de Putte, T., Pype, S., Huylebroeck, D. and Verschueren, K. (2005) Smicl is a novel Smad interacting protein and cleavage and polyadenylation specificity factor associated protein. Genes Cells, 10, 897-906.
