Runx1 and Runx2 cooperate during sternal morphogenesis

Abstract

SUMMARYChondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1 f/f mice and a1(II) Runx1 f/f mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and a1(II) DKO mice, respectively]. Prx1 Runx1 f/f mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, a1(II) Runx1 f/f mice and a1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of a1(II) collagen (Col2a1 -Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of a1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.

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

“…One explanation for this is that morphogenetic processes that are different between the sternum and long bones influence the phenotype differences. For example, during sternal development, bilateral sternal cartilage bars migrate towards the midline and fuse to form the sternum; this is followed by chondrocyte hypertrophy and ossification 55 , suggesting a critical role for cell migration during the development of the sternum. Interestingly, Foxc1 is expressed in the sternum primordium of the E12.5 mouse embryo 45 and several reports indicate that it is involved in the migration of various types of cells, including germ 56 , endothelial 57 and breast cancer cells 58 .…”

Profilin1 Regulates Sternum Development and Endochondral Bone Formation

“…Genetic Requirement for Pfn1 in Sternum DevelopmentCleft sternum is a subject of surgical repair in human, whereas its genetics or etiology has not been known to date (21,22). The sternum develops between E13.5 and E16.5 of mice embryos.…”

Runx1 and Runx3 Are Downstream Effectors of Nanog in Promoting Osteogenic Differentiation of the Mouse Mesenchymal Cell Line C3H10T1/2

“…From the up-regulated genes, we selected several genes as candidates that could regulate osteogenic differentiation as downstream effectors of Nanog. Among these genes, we focused here on Runt-related transcription factor (Runx)1 and Runx3, in consideration of both the log2Ratio (Runx1, 3.45; Runx3, 1.61) and findings gathered from the literature (Kimura et al, 2010;Liakhovitskaia et al, 2010;Lian et al, 2003;Smith et al, 2005;Soung do et al, 2007;Wang et al, 2005;Yamashiro et al, 2004;Yano et al, 2013;Yoshida et al, 2004).…”