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Subcellular localization

basal body, Nucleoplasm, Plasma membrane, Cytosol

Functional category

• ECM & connective tissue
• Non-motile cilium / primary cilium
• Trafficking (BBSome
• small GTPases
• vesicular transport
• ATPases)

Function

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. Merlin protein was localized in perichondral cells and chondrocytes at various differentiation stages (Figure 1C). In vitro, Merlin expression was observed in the primary chondrocytes and increased during hypertrophic differentiation, paralleling markers such as COL10, MMP13, and OPN (Figures S1A, S1B, and S1D). The expression pattern of Merlin suggests that it plays a role in limb development and chondrocyte differentiation. We quantified the length and number of PCs in both cultured primary chondrocytes in vitro, and sections of growth plates in vivo (Figures 5B–5E and S9A–S9D). While the length of PCs was slightly reduced in Merlin CKO cells, the incidence of ciliated cells remained unchanged both in vivo and in vitro (Figures 5B–5E and S9A–S9D)(40503937).