Bone morphology is regulated modularly by global and regional genetic programs

Abstract

Bone protrusions provide stable anchoring sites for ligaments and tendons and define the unique morphology of each long bone. Despite their importance, the mechanism by which superstructures are patterned is unknown. Here, we identify components of the genetic program that control the patterning of <i>Sox9</i>⁺/<i>Scx</i>⁺ superstructure progenitors in mouse and show that this program includes both global and regional regulatory modules. Using light-sheet fluorescence microscopy combined with genetic lineage labeling, we mapped the broad contribution of the <i>Sox9</i>⁺/<i>Scx</i>⁺ progenitors to the formation of bone superstructures. Then, by combining literature-based evidence, comparative transcriptomic analysis and genetic mouse models, we identified <i>Gli3</i> as a global regulator of superstructure patterning, whereas <i>Pbx1</i>, <i>Pbx2</i>, <i>Hoxa11</i> and <i>Hoxd11</i> act as proximal and distal regulators, respectively. Moreover, by demonstrating a dose-dependent pattern regulation in <i>Gli3</i> and <i>Pbx1</i> compound mutations, we show that the global and regional regulatory modules work in a coordinated manner. Collectively, our results provide strong evidence for genetic regulation of superstructure patterning, which further supports the notion that long bone development is a modular process.This article has an associated 'The people behind the papers' interview.