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

Abstract

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.

Evolving New Skeletal Traits by cis -Regulatory Changes in Bone Morphogenetic Proteins

“…Previous studies show that GDF6 can promote chondrogenesis (Erlacher et al, 1998; Gooch et al, 2002; Nochi et al, 2004), but can also act as inhibitor of osteogenesis (Shen et al, 2009; Clendenning et al, 2012). Digit bones form from cartilaginous precursors, and smaller toes in Gdf6 mutants likely reflects reduced chondrogenic activity in developing footplates, similar to the shortening of endochondral bones seen with mutations in other closely related GDF signaling molecules (Storm et al, 1994).…”

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

“…GDF6 also acts during embryogenesis to regulate cell differentiation. In the mouse, Gdf6 inhibits differentiation of the mesenchymal progenitors that develop into the coronal suture, and precocious differentiation of these cells results in fusion (60,61). Thus, in certain tissues, GDF6 can promote cell survival during development as well as regulate terminal differentiation.…”

Genetic advances in craniosynostosis

“…Also, the BMP2 -related intracellular osteogenic cascade is activated in calvarial cells isolated from prematurely fused sutures of affected individuals [Lattanzi et al, 2013]. The importance of the BMP pathway in the pathogenesis of CS is further corroborated by studies of animal models: BMP3 variants are found in brachycephalic dog breeds [Schoenebeck et al, 2012], mice with loss of BMP13 (also known as growth differentiation factor 6, Gdf6 ,) have coronal CS [Clendenning and Mortlock, 2012], while metopic CS is observed in mice with enhanced BMP signaling through constitutive activation of bmp receptor, type 1A ( Bmpr1a ) expression in cranial neural crest-derived structures [Komatsu et al, 2013]. In these models, craniosynostosis is believed to originate from an upregulation of Smad-dependent BMP signaling in the neural crest, resulting in enhanced ossification of the derived cranial bones [Komatsu et al, 2013].…”