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 :
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
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