Singh Jyoti, Verma Dipti, Sarkar Bappi, Paul Maimuna Sali, Mutsuddi Mousumi, Mukherjee Ashim
Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Open Biol. 2025 Apr;15(4):240247. doi: 10.1098/rsob.240247. Epub 2025 Apr 30.
The Notch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. To identify novel effectors of Notch signalling, we analysed the whole transcriptome of wing and eye imaginal discs in which an activated form of Notch was overexpressed. A LIM-homeodomain protein, Arrowhead (Awh), was identified as a novel candidate that plays a crucial role in Notch-mediated developmental events. alleles show strong genetic interaction with Notch pathway components. Awh loss-of-function upregulates Notch targets Cut and Wingless. Awh gain-of-function downregulates Notch targets by reducing the expression of the ligand Delta. Consequently, the expression of the Wingless effector molecule Armadillo and its downstream targets, Senseless and Vestigial, also gets downregulated. Awh overexpression leads to ectopic expression of , a segment polarity gene in the anterior region of wing disc, leading to patterning defects. Additionally, Notch gain-of-function-mediated neuronal defects get significantly rescued with Awh overexpression. Activated Notch inhibits Awh activity, suggesting a regulatory loop between Awh and Notch. Additionally, the defects caused by Awh gain-of-function were remarkably rescued by Chip, a LIM interaction domain containing transcriptional co-factor. The present study highlights the novel feedback regulation between Awh and Notch.
Notch信号通路是一种在进化上保守的信号系统，在不同的发育环境中影响一系列惊人的细胞命运决定。为了鉴定Notch信号的新效应物，我们分析了过表达激活形式Notch的翅和眼成虫盘的全转录组。一种LIM同源域蛋白，箭头蛋白（Awh），被鉴定为在Notch介导的发育事件中起关键作用的新候选物。等位基因与Notch信号通路成分表现出强烈的遗传相互作用。Awh功能丧失会上调Notch靶标Cut和无翅基因。Awh功能获得通过降低配体Delta的表达来下调Notch靶标。因此，无翅效应分子犰狳及其下游靶标感觉缺失和残翅的表达也会下调。Awh过表达导致翅盘前部区域的节段极性基因异位表达，导致模式缺陷。此外，Awh过表达显著挽救了Notch功能获得介导的神经元缺陷。激活的Notch抑制Awh活性，表明Awh和Notch之间存在调节环。此外，由Awh功能获得引起的缺陷被Chip显著挽救，Chip是一种含有LIM相互作用域的转录辅因子。本研究突出了Awh和Notch之间新的反馈调节。
