Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

Abstract

Functional movement and stability of the limb depends on an organized and fully integrated musculoskeletal system composed of skeleton, muscle, and tendon. Much of our current understanding of musculoskeletal development is based on studies that focused on the development and differentiation of individual tissues. Likewise, research on patterning events have been largely limited to the primary skeletal elements and the mechanisms that regulate soft tissue patterning, the development of the connections between tissues, and their interdependent development are only beginning to be elucidated. This review will therefore highlight recent exciting discoveries in this field, with an emphasis on tendon and muscle patterning and their integrated development with the skeleton and skeletal attachments.

Keywords: Muscle patterning; Musculoskeletal development; Tendon patterning.

Figure 1. Anatomy of dorsal and ventral autopod tendons of the limb

Intrinsic tendons are completely localized in the autopod along with their muscles while extrinsic tendons originate from muscles in the zeugopod.

Figure 2. Conceptual model for tendon modularity and development in the limb

Wrist tendon progenitors are induced at E12.5 integrating muscle to the skeleton or autopod tendon components. Induction is followed by elongation of the wrist tendon element in parallel with skeletal growth (E13.5–14.5).

Figure 3. Coordinated development of musculoskeletal tissues

The early stages of cartilage and muscle development are largely tissue autonomous (E9.5–E11.5). Integration begins at E12.5 with induction of attachment progenitors that mediate connection of muscle to the primary skeleton structure; cells of the attachment are then allocated to form the bone eminence and the tendon. While BMP4 is required for bone eminence differentiation, the molecular signals that regulate tendon differentiation and elongation are still unknown. Muscle differentiation is regulated by expression of MRFs in myogenic cells, but subsequent patterning depends on cells of the MCT. Enthesis progenitors are specified later in embryogenesis (and are likely derived from the initial attachment progenitor pool) and can be identified based on HH signaling. However, differentiation of the fibrocartilage enthesis occurs in postnatal stages, and depends on both HH signaling and active muscle forces. MRF: muscle regulatory factors; MCT: muscle connective tissue; HH: hedgehog.