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Growth Differentiation Factor-6  ( Gdf6 ) is a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules. Previous studies have shown that  Gdf6  plays a role in formation of a diverse subset of skeletal joints. In mice, loss of  Gdf6  results in fusion of the coronal suture, the intramembranous joint that separates the frontal and parietal bones. Although the role of GDFs in the development of cartilaginous limb joints has been studied, limb joints are developmentally quite distinct from cranial sutures and how  Gdf6  controls suture formation has remained unclear. In this study we show that coronal suture fusion in the  Gdf6−/−  mouse is due to accelerated differentiation of suture mesenchyme, prior to the onset of calvarial ossification.  Gdf6  is expressed in the mouse frontal bone primordia from embryonic day (E) 10.5 through 12.5. In the  Gdf6−/−  embryo, the coronal suture fuses prematurely and concurrently with the initiation of osteogenesis in the cranial bones. Alkaline phosphatase (ALP) activity and  Runx2  expression assays both showed that the suture width is reduced in  Gdf6+/−  embryos and is completely absent in  Gdf6−/−  embryos by E12.5. ALP activity is also increased in the suture mesenchyme of  Gdf6+/−  embryos compared to wild-type. This suggests  Gdf6  delays differentiation of the mesenchyme occupying the suture, prior to the onset of ossification. Therefore, although BMPs are known to promote bone formation,  Gdf6  plays an inhibitory role to prevent the osteogenic differentiation of the coronal suture mesenchyme.

The BMP Ligand Gdf6 Prevents Differentiation of Coronal Suture Mesenchyme in Early Cranial Development