Open AccessBone morphology is regulated modularly by global and regional genetic programs
Author(s) -
Shai Eyal,
Shiri Kult,
Sarah Rubin,
Sharon Krief,
Neta Felsenthal,
Kyriel M. Pineault,
Dena Leshkowitz,
Tomer-Meir Salame,
Yoseph Addadi,
Deneen M. Wellik,
Elazar Zelzer
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.167882
Subject(s) - biology , gli3 , sox9 , lineage (genetic) , regulator , superstructure , transcriptome , microbiology and biotechnology , progenitor cell , evolutionary biology , computational biology , genetics , transcription factor , gene , gene expression , stem cell , oceanography , repressor , geology
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 controls the patterning of Sox9+/Scx+ 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 Sox9+/Scx+ progenitors to the formation of bone superstructures. Then, by combining literature-based evidence, comparative transcriptomic analysis and genetic mouse models, we identified Gli3 as a global regulator of superstructure patterning, whereas Pbx1, Pbx2, Hoxa11 and Hoxd11 act as proximal and distal regulators, respectively. Moreover, by demonstrating a dose-dependent pattern regulation in Gli3 and Pbx1 compound mutations, we show that the global and regional regulatory modules work coordinately. 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.