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Concerted action of Msx1 and Msx2 in regulating cranial neural crest cell differentiation during frontal bone
Jun Han1, Mamoru Ishii, Pablo Bringas
1Center for Craniofacial Molecular Biology, School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA.
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.
Insights
Homeobox genes Msx1 and Msx2 are essential for frontal bone development in mice. Double mutants lacking both genes show no frontal bone formation, highlighting their critical role in osteogenesis.
Area of Science:
- Developmental Biology
- Genetics
- Craniofacial Development
Background:
- Homeobox genes Msx1 and Msx2 regulate cell proliferation and differentiation.
- Msx1 and Msx2 mutations cause craniofacial malformations, but single gene defects show mild frontal bone defects, suggesting functional compensation.
Purpose of the Study:
- To investigate the functional compensation between Msx1 and Msx2 in early frontal bone development.
- To determine the specific roles of Msx1 and Msx2 in the formation of the frontal bone.
Main Methods:
- Generation and analysis of Msx1(-/-);Msx2(-/-) double mutant mouse embryos.
- Assessment of cranial neural crest (CNC) cell migration and differentiation.
- Analysis of gene expression, including Runx2 and Bmp signaling pathways.
Main Results:
- Msx1(-/-);Msx2(-/-) embryos exhibited embryonic lethality between E17-E18 with complete absence of frontal bone.
- CNC migration was normal, but frontal mesenchyme differentiation and primordium establishment were defective.
- Msx genes are crucial for Runx2 expression in frontonasal CNC cells and osteogenic lineage differentiation.
Conclusions:
- Msx1 and Msx2 are essential and non-redundant for frontal bone osteogenesis.
- These genes are required for the differentiation of cranial neural crest cells into osteoblasts within the frontal bone primordium.
- The function of Msx genes in early frontal bone development is independent of the Bmp signaling pathway.
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