Transgenically ectopic expression of Bmp4 to the Msx1 mutant dental mesenchyme restores downstream gene expression but represses Shh and Bmp2 in the enamel knot of wild type tooth germ

Abstract

Bmp4 is a downstream gene of Msx1 in early mouse tooth development. In this study, we introduced the Msx1-Bmp4 transgenic allele to the Msx1 mutants in which tooth development is arrested at the bud stage in an effort of rescuing Msx1 mutant tooth phenotype in vivo. Ectopic expression of a Bmp4 transgene driven by the mouse Msx1promoter in the dental mesenchyme restored the expression of Lef-1 and Dlx2 but neither Fgf3 nor syndecan-1 in the Msx1 mutant molar tooth germ. The mutant phenotype of molar but not incisor could be partially rescued to progress to the cap stage. The Msx1-Bmp4 transgene was also able to rescue the alveolar processes and the neonatal lethality of the Msx1 mutants. In contrast, overexpression of Bmp4 in the wild type molar mesenchyme down-regulated Shh and Bmp2 expression in the enamel knot, the putative signaling center for tooth patterning, but did not produce a tooth phenotype. These results indicate that Bmp4 can bypass Msx1 function to partially rescue molar tooth development in vivo, and to support alveolar process formation. Expression of Shh and Bmp2 in the enamel knot may not represent critical signals for tooth patterning.

Msx homeobox gene family and craniofacial development

“…A non-cell autonomous secondary effect of Msx1 deficiency is the loss of Shh and Bmp2 expression in the dental epithelium [93]. The bud stage arrest is lifted upon the addition of exogenous BMP4 or by trangenic expression of Bmp4 thereby bypassing the need for Msx1 function [89,93,108]. As a result, tooth development proceeded past cap stage in vitro engendering a near complete rescue in kidney capsule cultures and a restoration of alveolar bone formation in transgenic mice [89,108,109].…”

“…The bud stage arrest is lifted upon the addition of exogenous BMP4 or by trangenic expression of Bmp4 thereby bypassing the need for Msx1 function [89,93,108]. As a result, tooth development proceeded past cap stage in vitro engendering a near complete rescue in kidney capsule cultures and a restoration of alveolar bone formation in transgenic mice [89,108,109]. Analysis of gene expression showed that Lef1, Dlx2, Shh and Bmp2 expression is restored following ectopic or exogenous BMP-4 expression.…”

“…It was previously believed that the cleft secondary palate observed in Msx1-deficient mice occurs as a consequence of a primary defect in tooth development [18,19,103]. This contention was disproved recently by functional assays using a transgenic mouse model where the Msx1 promoter directs the expression of human Bmp4 in developing tooth and palate in the Msx1 -/-background leading to rescue of neonatal lethality in some mice [62,93,108]. Notably, all of the surviving Msx1 -/-/Tg mice exhibited a closed palate although they still lacked teeth.…”

Quantitative genetics of cortical bone mass in healthy 10-year-old children from the Fels Longitudinal Study

“…Knockout and transgenic mouse models have contributed significantly to knowledge of the effects of single genes in bone regulation, such as the insulin-like growth factor-1 and bone morphogenetic protein-4 genes [65,66]. Highly inbred strains of mice provide a powerful means for investigating genetic influences over bone phenotypes [1,5,26,31,62].…”

Transgenic Mice Overexpressing BMP4 Develop a Fibrodysplasia Ossificans Progressiva (FOP)-Like Phenotype

“…10 Msx1-Bmp4 transgenic mice overexpressing human BMP4 under control of mouse Msx1 minimal promoter develop no visible abnormalities. 11 We report here a developmentally associated postnatal heterotopic os-sification mouse model: transgenic mice that overexpress BMP4 under the control of neuron-specific enolase (NSE) promoter. These transgenic mice develop severe postnatal heterotopic ossification, which closely recapitulates major FOP phenotypes.…”