Foxc1 integrates Fgf and Bmp signalling independently of twist or noggin during calvarial bone development

Abstract

Calvarial bone and suture development is under complex regulation where bone morphogenetic protein (Bmp) and fibroblast growth factor (Fgf) signalling interact with Msx2/Twist and Noggin and regulate frontal bone primordia proliferation and suture fusion, respectively. We have shown previously that the winged helix transcription factor Foxc1, which is necessary for calvarial bone development, is required for the Bmp regulation of Msx2. We now show that FGF2 regulates the expression of Foxc1, indicating that Foxc1 integrates Bmp and Fgf signalling pathways. We also show that Foxc1 is not needed for the acquisition of osteogenic potential or for the differentiation of osteoblasts.

The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification

“…The mechanism by which Foxc1 regulates skeletal development has previously been investigated from the viewpoint of intramembranous bone formation with particular focus on osteoblasts, not endochondral ossification. Thus, several groups have reported the importance of bone morphogenetic protein signalling and Msx2 in Foxc1-dependent calvarial bone development [46][47][48] . Although Alcian blue-positive nodule formation of mesenchymal cells isolated from Foxc1 lacZ embryos has been studied 45 , the molecular mechanisms by which Foxc1 controls endochondral formation are largely unknown.…”

Small Ubiquitin-like Modifier (SUMO) Modification Mediates Function of the Inhibitory Domains of Developmental Regulators FOXC1 and FOXC2

“…BMP7, SMAD2, TGF-B1, and WNT6 (57) as well as FGF19 (58) have been proposed for FOXC1. Although the relevant FOXC1 targets during craniofacial development are not fully defined, Msx2 is an interesting candidate (59,60). In this regard, enhanced FOXC1 activity due to loss of SUMO modification could result in abnormal up-regulation of Msx2 and could promote the development of abnormalities such as Boston type craniosynostosis.…”

Prevention of Premature Fusion of Calvarial Suture in GLI-Kruppel Family Member 3 (Gli3)-deficient Mice by Removing One Allele of Runt-related Transcription Factor 2 (Runx2)

“…6, A, d-f panels, and B, d-f panels). However, the expression of Noggin, which is induced by Bmp2 administration (8), was slightly up-regulated at the interfrontal suture of Gli3…”

“…Foxc1 is induced by Fgf and regulates the effects of Bmp signaling. It does this independently of the Bmp post-transcriptional repressor, Noggin, which is itself critical for suture patency (8,9). Foxc1 Ϫ/Ϫ mice exhibit defective calvarial osteogenesis with the calvarial bones remaining rudimentary at the sites of initial osteogenic condensations (10).…”