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ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development.

ABSTRACT: Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-? cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-?1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL-ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.

SUBMITTER: Osorio L

PROVIDER: S-EPMC6605798 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development.

Osório Liliana L Wu Xuewei X Wang Linsheng L Jiang Zhixin Z Neideck Carlos C Sheng Guojun G Zhou Zhongjun Z

The Journal of cell biology 20190606 7

Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in <i>Xenopus laevis</i> embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signa ...[more]

PMID: 31171630

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Project description:BackgroundNodal is an important determinant of the left-right (LR) body axis in bilaterians, specifying the right side in protostomes and non-chordate deuterostomes as opposed to the left side in chordates. Amphioxus represents an early-branching chordate group, rendering it especially useful for studying the character states that predate the origin of vertebrates. However, its anatomy, involving offset arrangement of axial structures, marked asymmetry of the oropharyngeal region, and, most notably, a mouth positioned on the left side, contrasts with the symmetric arrangement of the corresponding regions in other chordates.ResultsWe show that the Nodal signaling pathway acts to specify the LR axis in the cephalochordate amphioxus in a similar way as in vertebrates. At early neurula stages, Nodal switches from initial bilateral to the left-sided expression and subsequently specifies the left embryonic side. Perturbation of Nodal signaling with small chemical inhibitors (SB505124 and SB431542) alters expression of other members of the pathway and of left/right-sided, organ-specific genes. Upon inhibition, larvae display loss of the innate alternation of both somites and axons of peripheral nerves and loss of left-sided pharyngeal structures, such as the mouth, the preoral pit, and the duct of the club-shaped gland. Concomitantly, the left side displays ectopic expression of otherwise right-sided genes, and the larvae exhibit bilaterally symmetrical morphology, with duplicated endostyle and club-shaped gland structures.ConclusionsWe demonstrate that Nodal signaling is necessary for establishing the LR embryonic axis and for developing profound asymmetry in amphioxus. Our data suggest that initial symmetry breaking in amphioxus and propagation of the pathway on the left side correspond with the situation in vertebrates. However, the organs that become targets of the pathway differ between amphioxus and vertebrates, which may explain the pronounced asymmetry of its oropharyngeal and axial structures and the left-sided position of the mouth.

Dataset Information

ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development.

Publications

ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development.

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