IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-62003-6.html
   My bibliography  Save this article

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

Author

Listed:
  • Zhengfan Zheng

    (The University of Hong Kong)

  • Suisui Guo

    (The University of Hong Kong
    The Hong Kong University of Science and Technology)

  • Hoi Yau Tam

    (The University of Hong Kong)

  • Jingkai Wang

    (The University of Hong Kong)

  • Yanxia Rao

    (The University of Hong Kong
    Fudan University)

  • Man-Ning Hui

    (The University of Hong Kong
    The University of Hong Kong)

  • May Pui Lai Cheung

    (The University of Hong Kong)

  • Alan Wai Lun Leung

    (University of New Haven
    Quinniplac University)

  • Kelvin K. W. Wong

    (The University of Hong Kong)

  • Rakesh Sharma

    (The University of Hong Kong)

  • Jessica Aijia Liu

    (City University of Hong Kong)

  • Martin Cheung

    (The University of Hong Kong)

Abstract

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.

Suggested Citation

  • 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, 2025. "Determination of trunk neural crest cell fate and susceptibility to splicing perturbation by the DLC1-SF3B1-PHF5A splicing complex," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62003-6
    DOI: 10.1038/s41467-025-62003-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-62003-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-62003-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. André Corvelo & Martina Hallegger & Christopher W J Smith & Eduardo Eyras, 2010. "Genome-Wide Association between Branch Point Properties and Alternative Splicing," PLOS Computational Biology, Public Library of Science, vol. 6(11), pages 1-13, November.
    2. Nadjet Gacem & Anthula Kavo & Lisa Zerad & Laurence Richard & Stephane Mathis & Raj P. Kapur & Melanie Parisot & Jeanne Amiel & Sylvie Dufour & Pierre de la Grange & Veronique Pingault & Jean Michel V, 2020. "ADAR1 mediated regulation of neural crest derived melanocytes and Schwann cell development," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Constantin Cretu & Patricia Gee & Xiang Liu & Anant Agrawal & Tuong-Vi Nguyen & Arun K. Ghosh & Andrew Cook & Melissa Jurica & Nicholas A. Larsen & Vladimir Pena, 2021. "Structural basis of intron selection by U2 snRNP in the presence of covalent inhibitors," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Luisa Vigevani & André Gohr & Thomas Webb & Manuel Irimia & Juan Valcárcel, 2017. "Molecular basis of differential 3′ splice site sensitivity to anti-tumor drugs targeting U2 snRNP," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Fenghua Yang & Tong Bian & Xiechao Zhan & Zhe Chen & Zhihan Xing & Nicolas A. Larsen & Xiaofeng Zhang & Yigong Shi, 2023. "Mechanisms of the RNA helicases DDX42 and DDX46 in human U2 snRNP assembly," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Pablo Baeza-Centurión & Belén Miñana & Andre J. Faure & Mike Thompson & Sophie Bonnal & Gioia Quarantani & Joseph Clarke & Ben Lehner & Juan Valcárcel, 2025. "Deep indel mutagenesis reveals the regulatory and modulatory architecture of alternative exon splicing," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    3. Yaron Strauch & Jenny Lord & Mahesan Niranjan & Diana Baralle, 2022. "CI-SpliceAI—Improving machine learning predictions of disease causing splicing variants using curated alternative splice sites," PLOS ONE, Public Library of Science, vol. 17(6), pages 1-15, June.
    4. Linmao Sun & Yufeng Liu & Xinyu Guo & Tianming Cui & Chenghui Wu & Jie Tao & Cheng Cheng & Qi Chu & Changyong Ji & Xianying Li & Hongrui Guo & Shuhang Liang & Huanran Zhou & Shuo Zhou & Kun Ma & Ning , 2024. "Acetylation-dependent regulation of core spliceosome modulates hepatocellular carcinoma cassette exons and sensitivity to PARP inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Morgane Mabire & Pushpa Hegde & Adel Hammoutene & Jinghong Wan & Charles Caër & Rola Al Sayegh & Mathilde Cadoux & Manon Allaire & Emmanuel Weiss & Tristan Thibault-Sogorb & Olivier Lantz & Michèle Go, 2023. "MAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62003-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.