Hic1 identifies a specialized mesenchymal progenitor population in the embryonic limb responsible for bone superstructure formation

Abstract

The musculoskeletal system relies on the integration of multiple components with diverse physical properties, such as striated muscle, tendon, and bone, that enable locomotion and structural stability. This relies on the emergence of specialized, but poorly characterized, interfaces between these various elements during embryonic development. Within the appendicular skeleton, we show that a subset of mesenchymal progenitors (MPs), identified by Hic1, do not contribute to the primary cartilaginous anlagen but represent the MP population, whose progeny directly contribute to the interfaces that connect bone to tendon (entheses), tendon to muscle (myotendinous junctions), and the associated superstructures. Furthermore, deletion of Hic1 leads to skeletal defects reflective of deficient muscle-bone coupling and, consequently, perturbation of ambulation. Collectively, these findings show that Hic1 identifies a unique MP population that contributes to a secondary wave of bone sculpting critical to skeletal morphogenesis.

Keywords: CP: Developmental biology; chondrogenesis; congenital limb defects; enthesis; limb development; lineage tracing; mesenchymal progenitors; myotendinous junction; single-cell omics; skeletal development; transgenic models.