The Axenfeld-Rieger Syndrome Gene FOXC1 Contributes to Left-Right Patterning.
The Axenfeld-Rieger Syndrome Gene FOXC1 Contributes to Left-Right Patterning.
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DOI：
10.3390/genes12020170
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发表时间：
2021-01-26
期刊：
影响因子：
3.5
通讯作者：
Waskiewicz AJ
中科院分区：
文献类型：
--
作者：
Chrystal PW;French CR;Jean F;Havrylov S;van Baarle S;Peturson AM;Xu P;Crump JG;Pilgrim DB;Lehmann OJ;Waskiewicz AJ
侧板中胚层中节点-左- pitx2级联的精确时空表达建立了左右轴，这为正确的器官形成和功能提供了重要的线索。一个级联成分PITX2的突变，以及叉头转录因子FOXC1的突变，各自独立地引起一种称为Axenfeld-Rieger综合征（ARS）的多系统疾病。由于心脏受累是一种确定的ARS表型，并且由于左右模式中断可导致先天性心脏缺陷，我们在斑马鱼中研究了foxc1是否有助于器官侧边或位置。我们证明CRISPR/ cas9产生的foxc1a和foxc1b突变体表现出异常的心环，并且foxc1a−/−中心脏部位缺陷的患病率增加；foxc1b−−该等位。同样，双纯合子表现出肝脏和胰腺的同分异构体，这是肠道异常的关键特征。相对于中线的不对称内脏器官的位置也受到foxc1a和foxc1b mRNA过表达的干扰。此外，对foxc1突变体侧板中胚层中发现的左-右模式成分的分析，减少或消除了NODAL拮抗剂lefty2的表达。总之，这些数据揭示了foxc1对左右模式的新贡献，表明这一作用对foxc1基因剂量敏感，并为Axenfeld-Rieger综合征患者先天性心脏缺陷的发生率提供了一种合理的机制。
Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left–right axis, which provides vital cues for correct organ formation and function. Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld–Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left–right patterning can cause congenital heart defects, we investigated in zebrafish whether foxc1 contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated foxc1a and foxc1b mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in foxc1a−/−; foxc1b−/− homozygotes. Similarly, double homozygotes exhibit isomerism of the liver and pancreas, which are key features of abnormal gut situs. Placement of the asymmetric visceral organs relative to the midline was also perturbed by mRNA overexpression of foxc1a and foxc1b. In addition, an analysis of the left–right patterning components, identified in the lateral plate mesoderm of foxc1 mutants, reduced or abolished the expression of the NODAL antagonist lefty2. Together, these data reveal a novel contribution from foxc1 to left–right patterning, demonstrating that this role is sensitive to foxc1 gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld–Rieger syndrome patients.
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影响因子：
30.8
作者：
Aldinger, Kimberly A.;Lehmann, Ordan J.;Hudgins, Louanne;Chizhikov, Victor V.;Bassuk, Alexander G.;Ades, Lesley C.;Krantz, Ian D.;Dobyns, William B.;Millen, Kathleen J.
通讯作者：
Millen, Kathleen J.
影响因子：
3.7
作者：
Deng X;Zhou J;Li FF;Yan P;Zhao EY;Hao L;Yu KJ;Liu SL
通讯作者：
Liu SL
影响因子：
4.6
作者：
Campbell, Evan P.;Quigley, Ian K.;Kintner, Chris
通讯作者：
Kintner, Chris
影响因子：
2
作者：
Gripp, Karen W.;Hopkins, Elizabeth;Salvin, Jonathan
通讯作者：
Salvin, Jonathan
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF