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Abstract
Craniofacial development is a program exquisitely orchestrated by tissue contributions and regulation of genes expression. The basic helix–loop–helix (bHLH) transcription factor Twist1 expressed in the skeletal mesenchyme is a key regulator of craniofacial development playing an important role during osteoskeletogenesis. This study investigates the postnatal impact of Twist1 haploinsufficiency on the osteoskeletal ability and regeneration on two calvarial bones arising from tissues of different embryonic origin: the neural crest-derived frontal and the mesoderm-derived parietal bones. We show that Twist1 haplonsufficiency as well Twist1-sh-mediated silencing selectively enhanced osteogenic and tissue regeneration ability of mesoderm-derived bones. Transcriptomic profiling, gain-and loss-of-function experiments revealed that Twist1 haplonsufficiency triggers its selective activity on mesoderm-derived bone through a sharp downregulation of the bone-derived hormone Fgf23 that is upregulated exclusively in wild-type parietal bone.
Highlights
The mammalian skull vault is a structure formed by five intramembranous flat bones: the paired frontal and parietal bones and the unpaired interparietal bone (Morriss-Kay, 2001)
The analysis obtained by Reverse Transcription (RT)-PCR revealed a distinct expression pattern between the frontal and parietal bones, which was characterized, starting from day pN2 by a significant increase of Twist1 expression in the mesodermal-derived parietal bone which reach a peak at day postnatal day 21 (pN21), followed by downregulation at later time points
Our results suggested that the osteoskeletal phenotype observed in Twist1+/− parietal bone and parietal osteoblasts (POb) is at least in part mediated by Fgf23 downregulation
Summary
The mammalian skull vault is a structure formed by five intramembranous flat bones: the paired frontal and parietal bones and the unpaired interparietal bone (Morriss-Kay, 2001). The adjacent osteogenic fronts of these intramembranous bones form the sutures, which accommodate the growth of skull vault and underlying brain. The morphogenesis of the skull vault is accomplished in two phases: the first is defined by the genesis, migration and early specification of skeletogenic precursor cells. The mixed developmental origin of the mammalian skull vault has been clearly defined by employing a Wnt1-Cre/conditional LacZ reporter R26R double transgene mouse tracing exclusively neural crest cells, and showing that the frontal and squamosal bones are neural crest-derived, while the parietal bone is of mesoderm-derived (Jiang et al, 2002). Yoshida et al (2008) elegantly validated the same dual embryonic origin of
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