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<p>Introns have expanded dramatically during evolution, and while their internal sequences have greatly diverged, the potential function of ultraconserved RNA motifs remains an important, unanswered question. Sharing the sequence with the utilized 5’ splice sites (5’SSs), pseudo-5’SSs are widespread in introns but are never spliced. We searched homologous introns and identified eight ultraconserved pseudo-5’SSs (UCP-5’SSs). The most conserved one resides in the animal <i>ENOX1/Enox</i> genes that are involved in plasma membrane electron transport and cell enlargement. In vivo deletion of this 9-nt UCP-5’SS in <i>Drosophila</i> results in a significantly enlarged ovary and increased fecundity. We demonstrate that this UCP-5’SS is a silencer for alternative splicing (AS) regulation of an upstream ultraconserved essential exon through interaction with the U1 snRNP-core proteins. The AS changes are observed in all the tested <i>Drosophila</i> mutants from the dTOR and Insulin-like pathways. Remarkably, loss of this UCP-5’SS significantly mitigates the changes. Multiple-source human cells treated with the mTOR/Insulin pathway inhibitors also change the AS and specifically increase the translation of U1-70K, suggesting remarkable conservation of this mechanism. This study reveals an ultraconserved regulatory network in which a short intronic RNA element functions as a sensor of TOR-related pathways during ovarian development.</p>

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An ultraconserved pseudo 5’ splice site fine-tunes development by regulating alternative splicing within TOR-related pathways

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Zhan Ding,
  • Zhuo-Ya Fang,
  • Hao Li,
  • Xi-Ping Jiang,
  • Yun-Long Xie,
  • Wen-Xiu Bian,
  • Yan-Ting Wu,
  • Xiao-Yi Lu,
  • Bao-Liang Song,
  • Yu-Jie Fan,
  • Yong-Zhen Xu

摘要

Introns have expanded dramatically during evolution, and while their internal sequences have greatly diverged, the potential function of ultraconserved RNA motifs remains an important, unanswered question. Sharing the sequence with the utilized 5’ splice sites (5’SSs), pseudo-5’SSs are widespread in introns but are never spliced. We searched homologous introns and identified eight ultraconserved pseudo-5’SSs (UCP-5’SSs). The most conserved one resides in the animal ENOX1/Enox genes that are involved in plasma membrane electron transport and cell enlargement. In vivo deletion of this 9-nt UCP-5’SS in Drosophila results in a significantly enlarged ovary and increased fecundity. We demonstrate that this UCP-5’SS is a silencer for alternative splicing (AS) regulation of an upstream ultraconserved essential exon through interaction with the U1 snRNP-core proteins. The AS changes are observed in all the tested Drosophila mutants from the dTOR and Insulin-like pathways. Remarkably, loss of this UCP-5’SS significantly mitigates the changes. Multiple-source human cells treated with the mTOR/Insulin pathway inhibitors also change the AS and specifically increase the translation of U1-70K, suggesting remarkable conservation of this mechanism. This study reveals an ultraconserved regulatory network in which a short intronic RNA element functions as a sensor of TOR-related pathways during ovarian development.