Peeters Hilde, Voz Marianne L, Verschueren Kristin, De Cat Bart, Pendeville Hélène, Thienpont Bernard, Schellens Ann, Belmont John W, David Guido, Van De Ven Wim J M, Fryns Jean-Pierre, Gewillig Marc, Huylebroeck Danny, Peers Bernard, Devriendt Koen
Department of Human Genetics, Clinical Genetics Unit, University of Leuven, Belgium.
Hum Mol Genet. 2006 Nov 15;15(22):3369-77. doi: 10.1093/hmg/ddl413. Epub 2006 Oct 12.
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.
在理解脊椎动物模型左右不对称背后的分子机制方面已取得显著进展，但对于人类左右轴的形成却知之甚少。此前，我们通过对一名内脏异位患者的新发易位断点区域进行定位克隆，将SESN1（也称为PA26）鉴定为内脏异位的候选基因。在本研究中，我们通过斑马鱼sesn1基因敲低模型表明，Sesn1是正常胚胎左右决定所必需的。在该模型中，与脊椎动物左右不对称相关的发育缺陷和基因表达数据表明Sesn1在介导Nodal信号传导中发挥作用。在侧板中胚层中，Nodal信号传导在脊椎动物左右轴形成中起核心作用，并由FoxH1转录诱导介导。与此一致的是，我们表明Sesn1与FoxH1或含FoxH1的复合物发生物理相互作用。对234名单发性内脏异位患者的突变分析未发现突变，表明这些只是人类内脏异位的罕见原因。在本研究中，我们将SESN1鉴定为脊椎动物左右不对称所必需的基因以及介导Nodal信号传导的新因子。
