Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone development

Abstract

The homeobox genes Msx1 and Msx2 function as transcriptional regulators that control cellular proliferation and differentiation during embryonic development. Mutations in the Msx1 and Msx2 genes in mice disrupt tissue-tissue interactions and cause multiple craniofacial malformations. Although Msx1 and Msx2 are both expressed throughout the entire development of the frontal bone, the frontal bone defect in Msx1 or Msx2 null mutants is rather mild, suggesting the possibility of functional compensation between Msx1 and Msx2 during early frontal bone development. To investigate this hypothesis, we generated Msx1(-/-);Msx2(-/-) mice. These double mutant embryos died at E17 to E18 with no formation of the frontal bone. There was no apparent defect in CNC migration into the presumptive frontal bone primordium, but differentiation of the frontal mesenchyme and establishment of the frontal primordium was defective, indicating that Msx1 and Msx2 genes are specifically required for osteogenesis in the cranial neural crest lineage within the frontal bone primordium. Mechanistically, our data suggest that Msx genes are critical for the expression of Runx2 in the frontonasal subpopulation of cranial neural crest cells and for differentiation of the osteogenic lineage. This early function of the Msx genes is likely independent of the Bmp signaling pathway.

Foxc1 controls the growth of the murine frontal bone rudiment by direct regulation of a Bmp response threshold of Msx2

“…It is well established that Bmp signaling controls the differentiation of osteogenic precursor cells in the frontal and parietal bone rudiments (Kim et al, 1998). There is also evidence that reduced dose of Msx1/2 results in reduced numbers of osteogenic precursor cells in calvarial bone rudiments, and reduced calvarial bone growth (Ishii et al, 2003;Han et al, 2007). Given that Msx genes are known to be transcriptional effectors of Bmp signaling (Vainio et al, 1993;Graham et al, 1994; Bei and Maas, 1998), our finding that Foxc1 negatively regulates the Bmp inducibility of Msx2 in the mesenchyme of the supraorbital ridge and in cultured cranial neural crest cells suggests that Foxc1 controls a Bmp threshold response of Msx2.…”

“…Humans with heterozygous loss of MSX2 function are similarly affected (Wilkie et al, 2000). Combination Msx1/2 mutants exhibit agenesis of the frontal and parietal bones (Han et al, 2007). Msx2 is regulated by the Bmp pathway through an upstream Bmp responsive enhancer element (Brugger et al, 2004).…”

Mesenchyme-dependent BMP signaling directs the timing of mandibular osteogenesis

“…Furthermore, SMADs physically interact with RUNX2 to potentiate osteoblast-specific gene expression (Lee et al, 2000;Ito et al, 2002). Finally, other targets of BMP signaling, such as Msx1 (Suzuki et al, 1997;Tribulo et al, 2003), are required for proper epithelial-mesenchymal interactions in the mandible (Chen et al, 1996;Bei and Maas, 1998;Han et al, 2007) and affect skeletogenesis (Satokata and Maas, 1994).…”

Msx2 Exerts Bone Anabolism via Canonical Wnt Signaling

“…Moreover, Msx2 Ϫ/Ϫ mice exhibit a global, low turnover osteopenia (9). Simultaneous deletion of both Msx2 and Msx1, a homologous Msx gene family member, results in the complete absence of craniofacial bone (9,11). Furthermore, a nonsynonymous CCC to CAC mutation at the 7th codon of the Msx2 homeodomain causes Boston-type autosomal dominant craniosynostosis, characterized by precocious mineralization and differentiation of osteoblasts in the calvarial suture (12).…”