Multiple Notch ligands in the synchronization of the segmentation clock

Marcos Wappner, Koichiro Uriu, Andrew C. Oates, Luis G. Morelli
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Abstract

Notch signaling is a ubiquitous and versatile intercellular signaling system that drives collective behaviors and pattern formation in biological tissues. During embryonic development, Notch is involved in generation of collective biochemical oscillations that form the vertebrate body segments, and its failure results in embryonic defects. Notch ligands of the Delta family are key components of this collective rhythm, but it is unclear how different Delta ligands with distinct properties contribute to relaying information among cells. Motivated by the zebrafish segmentation clock, in this work we propose a theory describing interactions between biochemical oscillators, where Notch receptor is bound by both oscillatory and nonoscillatory Delta ligands. Based on previous in vitro binding studies, we first consider Notch activation by Delta dimers. This hypothesis is consistent with experimental observations in conditions of perturbed Notch signaling. Then we test an alternative hypothesis where Delta monomers directly bind and activate Notch, and show that this second model can also describe the experimental observations. We show that these two hypotheses assign different roles for a non-oscillatory ligand, as a binding partner or as a baseline signal. Finally, we discuss experiments to distinguish between the two scenarios. Broadly, this work highlights how a multiplicity of ligands may be harnessed by a signaling system to generate versatile responses.
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分割时钟同步过程中的多种 Notch 配体
在胚胎发育过程中,Notch参与了形成脊椎动物体节的集体生物化学振荡的产生,如果Notch失效,就会导致胚胎缺陷。Delta家族的Notch配体是这种集体节律的关键组成部分,但目前还不清楚具有不同特性的不同Deltal配体是如何在细胞间传递信息的。受斑马鱼分割时钟的启发,我们在这项工作中提出了描述生化振荡器之间相互作用的理论,其中 Notchreceptor 同时与振荡和非振荡 Delta 配体结合。基于之前的体外结合研究,我们首先考虑了 Notch 被 Delta 二聚体激活的情况。这一假设与 Notch 信号传导紊乱条件下的实验观察结果一致。然后,我们检验了另一种假设,即 Delta 单体直接结合并激活 Notch,结果表明第二种模型也能描述实验观察结果。我们表明,这两种假设赋予了非振荡配体不同的角色,即作为结合伙伴或作为基线信号。最后,我们讨论了区分这两种情况的实验。从广义上讲,这项工作强调了信号系统如何利用配体的多样性来产生多变的反应。
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