Wu Shali, Bian Yan, Zhang Cui, Liu Kaixin, Sun Fuju, Chen Erman, Zhou Chenhe, Yu Luyang, Chen Guiqian, Wu Mengrui
Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China.
Department of Cell and Developmental Biology, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310000, China; Zhejiang University-Lishui City Joint Innovation Center for Life and Health, Lishui, Zhejiang 323000, China.
Cell Rep. 2025 Jun 24;44(6):115849. doi: 10.1016/j.celrep.2025.115849. Epub 2025 Jun 10.
Hedgehog (HH) signaling, transduced at the primary cilium, plays a crucial role in limb longitudinal growth and digit formation, but its involvement in thumb development has been underestimated. This study identifies Merlin (Nf2) as a critical regulator of limb development, modulating the ciliary trafficking of the HH receptor, Smoothened. Merlin is predominantly expressed in limb buds and growth plates. Conditional knockout of Merlin in limb mesenchyme in mice results in dwarfism, brachydactyly, and thumb hypoplasia, with transcriptomic profiling and molecular analyses revealing disrupted HH signaling. Mechanistically, Merlin interacts with ARF6 to regulate the ciliary transport of Smoothened via RAB11 vesicles. Importantly, pharmacological enhancement of HH signaling significantly corrected the limb defects caused by Merlin deletion. These findings highlight the essential role of Merlin in regulating longitudinal limb growth and thumb morphogenesis via primary cilium-HH signaling, suggesting potential therapeutic strategies for related limb dysplasias.
在初级纤毛处转导的刺猬信号通路（HH信号通路）在肢体纵向生长和指（趾）形成中起关键作用，但其在拇指发育中的作用一直被低估。本研究确定了Merlin（Nf2）是肢体发育的关键调节因子，可调节HH受体Smoothened的纤毛运输。Merlin主要在肢体芽和生长板中表达。在小鼠肢体间充质中条件性敲除Merlin会导致侏儒症、短指畸形和拇指发育不全，转录组分析和分子分析显示HH信号通路受到破坏。从机制上讲，Merlin与ARF6相互作用，通过RAB11囊泡调节Smoothened的纤毛运输。重要的是，HH信号通路的药理学增强显著纠正了由Merlin缺失引起的肢体缺陷。这些发现突出了Merlin在通过初级纤毛-HH信号通路调节肢体纵向生长和拇指形态发生中的重要作用，为相关肢体发育异常提示了潜在的治疗策略。
