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Merlin Controls Limb Development and Thumb Formation by Regulating Primary Cilia-Hedgehog Signaling

GSE295650 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2025/05/20 Platform GPL24247
Summary
Hedgehog (HH) signaling, transduced at the primary cilium, plays a crucial role in limb longitudinal growth and digit formation, yet its involvement in thumb development has been underestimated. This study identifies Merlin (Nf2) as a novel 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 cilia-HH signaling, suggesting potential therapeutic strategies for related limb dysplasias.
Published in
Merlin controls limb development and thumb formation by regulating primary cilium-hedgehog signaling
Wu S, Bian Y, Zhang C et al. · Cell reports 2025 · PMID 40503937 · doi:10.1016/j.celrep.2025.115849
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Also filed as BioProject PRJNA1255523 and SRA study SRP581278. Searching any of these in the dataset finder brings you back here.

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