Fig. 10.

A modular model for long bone development and superstructure patterning. (A) Superstructure initiation is preceded by formation of the cartilaginous substructures derived from primary Sox9⁺ progenitors. (B) Subsequent to substructure differentiation, a secondary wave of de novo specification produces Sox9⁺/Scx⁺ superstructure progenitors. This second specification wave occurs in juxtaposition to the substructure at different time points during embryogenesis and is regulated by the TGFβ signaling pathway. The initial spatial patterning of superstructure progenitors is regulated by both global and regional molecular players, such as Gli3 or Pbx and Hox genes, respectively. (C) Following specification, patterning and condensation of the superstructure precursors, they differentiate and become integral to the substructure anlagen, thus producing a complex three-dimensional cartilaginous template that is unique to each long bone. Differentiation of the superstructure is regulated by intrinsic BMP4 signaling and extrinsic mechanical stimuli. (D) Finally, ossification of the substructure, and later of the superstructures, will give rise to the morphology of the mature long bone. D, distal; P, proximal.