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

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 and Martin Cheung ()
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Zhengfan Zheng: The University of Hong Kong
Suisui Guo: The University of Hong Kong
Hoi Yau Tam: The University of Hong Kong
Jingkai Wang: The University of Hong Kong
Yanxia Rao: The University of Hong Kong
Man-Ning Hui: The University of Hong Kong
May Pui Lai Cheung: The University of Hong Kong
Alan Wai Lun Leung: University of New Haven
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

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62003-6

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