Wnt/β-Catenin coordinates muscle spindle development by regulating capsule differentiation, intrafusal fiber nuclei aggregation and proprioceptive nerve endings

Proprioception is essential for regulating posture, coordinating movements, and maintaining musculoskeletal integrity. The muscle spindle, a mechanosensory organ composed of several types of tissues, detects stretch, forming proprioceptive awareness. Despite its significance, the molecular mechanisms underlying the coordinated development of the different tissues composing the spindle remain unclear. Here we show that Wnt ligands and their Fzd receptors are expressed in the developing spindle. Similarly, β-catenin is active in both the spindle capsule and intrafusal fibers throughout their development. Embryonic deletion of β-catenin from these tissues impaired capsule cell differentiation, intrafusal fiber nuclei organization, and proprioceptive nerve ending morphology. Postnatal deletion of β-catenin solely in intrafusal fibers results in abnormal proprioceptive nerve endings, suggesting both cell-autonomous and cell-non-autonomous roles of β-catenin in muscle spindle development. Our subsequent RNA transcriptome analysis of the β-catenin mutant spindle not only provides a molecular mechanism underlying the role of β-catenin in spindle development, but also expands the repertoire of molecules involved in spindle biology. By exposing a vast repertoire of new molecules involving all spindle tissues, our transcriptome could serve as a resource and benchmark for future discoveries in spindle biology. Collectively, our findings position the Wnt/β-catenin pathway as a central regulator with cell-autonomous and cell-non-autonomous roles, coordinating the diverse tissues of the spindle into a functional organ. Our transcriptome data further provide insight into spindle biology through a set of newly discovered molecules.