Merlin controls limb development and thumb formation by regulating primary cilium-hedgehog signaling.

IF 6.9 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-06-24 Epub Date: 2025-06-10 DOI:10.1016/j.celrep.2025.115849

Shali Wu, Yan Bian, Cui Zhang, Kaixin Liu, Fuju Sun, Erman Chen, Chenhe Zhou, Luyang Yu, Guiqian Chen, Mengrui Wu

{"title":"Merlin controls limb development and thumb formation by regulating primary cilium-hedgehog signaling.","authors":"Shali Wu, Yan Bian, Cui Zhang, Kaixin Liu, Fuju Sun, Erman Chen, Chenhe Zhou, Luyang Yu, Guiqian Chen, Mengrui Wu","doi":"10.1016/j.celrep.2025.115849","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"44 6","pages":"115849"},"PeriodicalIF":6.9000,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2025.115849","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/10 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

Merlin通过调节初级刺猬纤毛信号传导来控制肢体发育和拇指形成。

Hedgehog （HH）信号转导于初级纤毛，在肢体纵向生长和手指形成中起着至关重要的作用，但其在拇指发育中的作用一直被低估。本研究确定了Merlin （Nf2）作为肢体发育的关键调节因子，调节HH受体的纤毛运输。Merlin主要在肢芽和生长板中表达。小鼠肢体间充质Merlin的条件敲除会导致侏儒症、短指畸形和拇指发育不全，转录组学分析和分子分析显示HH信号被破坏。在机制上，Merlin与ARF6相互作用，通过RAB11+囊泡调节Smoothened纤毛运输。重要的是，HH信号的药理增强可显著纠正由Merlin缺失引起的肢体缺陷。这些发现强调了Merlin在通过初级纤毛hh信号调节纵向肢体生长和拇指形态发生中的重要作用，为相关肢体发育不良提供了潜在的治疗策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.