Long bones, such as the humerus, are thought to form in a modular process. The cylindrical part of the bone substructure is derived from Sox9-expressing progenitors, and subsequently cells that co-express Sox9 and Scx form superstructures protruding from the bone surface which provide sites for ligaments and tendons to attach. Although bone shape is clearly important for function, the molecular mechanisms that mediate bone morphology are poorly understood. Now, Elazar Zelzer and colleagues identify regulators of the formation and patterning of bone superstructures. By focusing on Gli3 null and conditional knockout mutant mice, the authors find a variety of superstructure malformations and an abnormal distribution of Sox9/Scx double-positive cells. Together, these data indicate that Gli3 is a global regulator for superstructure patterning. The authors also use transcriptome profiling of spatially isolated double-positive progenitors to identify local regulators of proximal and distal patterning, such as Pbx1/2 and Hoxa11/Hoxd11, respectively. Finally, they demonstrate that in Gli3 and Pbx1 compound mutants, such patterning is dose-dependent, suggesting an interaction between the global and regional regulatory modules. Combined, these results support a model for modular skeletogenesis and provide new insights for the morphogenesis and patterning of long bones.
