Altered bone growth dynamics prefigure craniosynostosis in a zebrafish model of Saethre-Chotzen syndrome.

Camilla S Teng,J Gage Crump,Mia Brockop,Man-Chun Ting,Robert E Maxson,D'Juan T Farmer

doi:10.7554/elife.37024

Abstract

Cranial sutures separate the skull bones and house stem cells for bone growth and repair. In Saethre-Chotzen syndrome, mutations in TCF12 or TWIST1 ablate a specific suture, the coronal. This suture forms at a neural-crest/mesoderm interface in mammals and a mesoderm/mesoderm interface in zebrafish. Despite this difference, we show that combinatorial loss of TCF12 and TWIST1 homologs in zebrafish also results in specific loss of the coronal suture. Sequential bone staining reveals an initial, directional acceleration of bone production in the mutant skull, with subsequent localized stalling of bone growth prefiguring coronal suture loss. Mouse genetics further reveal requirements for Twist1 and Tcf12 in both the frontal and parietal bones for suture patency, and to maintain putative progenitors in the coronal region. These findings reveal conservation of coronal suture formation despite evolutionary shifts in embryonic origins, and suggest that the coronal suture might be especially susceptible to imbalances in progenitor maintenance and osteoblast differentiation.

Highlights

Craniofacial anomalies are among the most common congenital defects, encompassing cleft lip and palate, facial malformations, and abnormalities in the flat bones forming the top of the skull
Twist1 function must be perturbed within both neural crest- and mesoderm-derived bones, and not just the mesodermderived postnatal sutural mesenchyme, to prevent suture formation. We find that these altered bone growth dynamics may be due to changes in osteoblast proliferation and eventual depletion of Gli1+ and Gremlin1+ putative bone progenitors prior to the fusion of the bones. These findings demonstrate that Tcf12 and Twist1 have a conserved early function during skull bone growth to regulate the sustained production of osteoblasts, possibly through maintenance of osteoprogenitors, and that the coronal suture is sensitive to defects in this process
We investigated whether suture defects in tcf12; twist1b mutants might result from an earlier misregulation of skull bone growth, to which the coronal suture might be sensitive

Summary

Introduction

Craniofacial anomalies are among the most common congenital defects, encompassing cleft lip and palate, facial malformations, and abnormalities in the flat bones forming the top of the skull. The similarity in the genetic interaction between Twist and Tcf in mice, humans, and fish, despite differences in the cell lineages that give rise to the bones, suggests that the underlying processes of coronal suture development and craniosynostosis are deeply conserved. We find that these altered bone growth dynamics may be due to changes in osteoblast proliferation and eventual depletion of Gli1+ and Gremlin1+ putative bone progenitors prior to the fusion of the bones These findings demonstrate that Tcf and Twist have a conserved early function during skull bone growth to regulate the sustained production of osteoblasts, possibly through maintenance of osteoprogenitors, and that the coronal suture is sensitive to defects in this process

Results

Discussion

Materials and methods

Funding Funder