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<p>How the ubiquitously expressed splicing factors specifically regulate neural crest (NC) development and enhance their vulnerability to splicing perturbations remain poorly understood. Here, we show that NC-specific DLC1, partnering with SF3B1-PHF5A splicing complex, are crucial for determining avian trunk NC cell fate by regulating the splicing of NC specifiers <i>SOX9</i> and <i>SNAI2</i> pre-mRNAs rather than their upstream regulators <i>BMP4</i>, <i>WNT1</i>, and <i>PAX7</i>. Mechanistically, SF3B1-PHF5A binds to the intronic branch site (BS) sequences of all factors, while DLC1 interacts with a specific motif near the BS sequences of <i>SOX9</i> and <i>SNAI2</i>, thereby determining their functional specificity in NC specification. Moreover, DLC1 increases NC cells’ vulnerability to splicing modulator pladienolide B&#xa0;(PB) by reducing the binding capacity of the SF3B1-PHF5A splicing complex to the shorter length of both <i>SOX9</i> intron 2 and <i>SNAI</i>2 intron 1, which possess weaker polypyrimidine tract 3’ of the BS sequence, resulting in intron retention and loss of NC progenitors. Conversely, somite specific SLU7-SF3B1-PHF5A splicing complex regulates <i>SOX9</i> and <i>SNAI2</i> expression and imparts resistance to PB. Our data reveal the cell-type specific splicing complexes with distinct vulnerabilities to PB, highlighting the critical role of the DLC1-SF3B1-PHF5A in determining trunk NC cell fate and enhancing its susceptibility to splicing perturbation.</p>

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Determination of trunk neural crest cell fate and susceptibility to splicing perturbation by the DLC1-SF3B1-PHF5A splicing complex

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月21日

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  • Zhengfan Zheng,
  • Suisui Guo,
  • Hoi Yau Tam,
  • Jingkai Wang,
  • Yanxia Rao,
  • Man-Ning Hui,
  • May Pui Lai Cheung,
  • Alan Wai Lun Leung,
  • Kelvin K. W. Wong,
  • Rakesh Sharma,
  • Jessica Aijia Liu,
  • Martin Cheung

摘要

How the ubiquitously expressed splicing factors specifically regulate neural crest (NC) development and enhance their vulnerability to splicing perturbations remain poorly understood. Here, we show that NC-specific DLC1, partnering with SF3B1-PHF5A splicing complex, are crucial for determining avian trunk NC cell fate by regulating the splicing of NC specifiers SOX9 and SNAI2 pre-mRNAs rather than their upstream regulators BMP4, WNT1, and PAX7. Mechanistically, SF3B1-PHF5A binds to the intronic branch site (BS) sequences of all factors, while DLC1 interacts with a specific motif near the BS sequences of SOX9 and SNAI2, thereby determining their functional specificity in NC specification. Moreover, DLC1 increases NC cells’ vulnerability to splicing modulator pladienolide B (PB) by reducing the binding capacity of the SF3B1-PHF5A splicing complex to the shorter length of both SOX9 intron 2 and SNAI2 intron 1, which possess weaker polypyrimidine tract 3’ of the BS sequence, resulting in intron retention and loss of NC progenitors. Conversely, somite specific SLU7-SF3B1-PHF5A splicing complex regulates SOX9 and SNAI2 expression and imparts resistance to PB. Our data reveal the cell-type specific splicing complexes with distinct vulnerabilities to PB, highlighting the critical role of the DLC1-SF3B1-PHF5A in determining trunk NC cell fate and enhancing its susceptibility to splicing perturbation.