Hox11 genes establish synovial joint organization and phylogenetic characteristics in developing mouse zeugopod skeletal elements

Abstract

SUMMARYHox11 genes are essential for zeugopod skeletal element development but their roles in synovial joint formation remain largely unknown. Here, we show that the elbow and knee joints of mouse embryos lacking all Hox11 paralogous genes are specifically remodeled and reorganized. The proximal ends of developing mutant ulna and radius elements became morphologically similar and formed an anatomically distinct elbow joint. The mutant ulna lacked the olecranon that normally attaches to the triceps brachii muscle tendon and connects the humerus to the ulna. In its place, an ulnar patella-like element developed that expressed lubricin on its ventral side facing the joint and was connected to the triceps muscle tendon. In mutant knees, both tibia and fibula fully articulated with an enlarged femoral epiphyseal end that accommodated both elements, and the neo-tripartite knee joint was enclosed in a single synovial cavity and displayed an additional anterior ligament. The mutant joints also exhibited a different organization of the superficial zone of articular cartilage that normally exerts an anti-friction function. In conclusion, Hox11 genes co-regulate and coordinate the development of zeugopod skeletal elements and adjacent elbow and knee joints, and dictate joint identity, morphogenesis and anatomical and functional organization. Notably, the ulnar patella and tripartite knee joints in the mouse mutants actually characterize several lower vertebrates, including certain reptiles and amphibians. The re-emergence of such anatomical structures suggests that their genetic blueprint is still present in the mouse genome but is normally modified to the needs of the mammalian joint-formation program by distinct Hox11 function.

On the development of the patella

“…For example, in contrast to patella development, Mikic et al reported that the plantar tarsal sesamoids do not form in paralyzed chicks (Mikic et al, 2000). Moreover, there is a growing body of evidence suggesting that early patterning genes, such as Hox9 (Fromental-Ramain et al, 1996), Hox10 (Carpenter et al, 1997), Hox11 (Koyama et al, 2010;Small and Potter, 1993) and Tbx4 (Bongers et al, 2004) affect other aspects of sesamoid development such as their number, distribution and size.…”

The Skeletal site‐specific role of connective tissue growth factor in prenatal osteogenesis

“…Why CTGF ablation only affects the zeugopod region could be due to changes in skeletal patterning, mechanobiological alterations, or a combination of the two. One of the key classes of genes involved in limb development includes the Hox genes, and it has been shown that specific mutations in Hoxa11, Hoxc11, and Hoxd11 deleteriously affect normal development of the zeugopod (Wellik and Capecchi, 2003; Zakany and Duboule, 2007; Koyama et al, 2010). Mechanobiological cues are also important in proper limb development, where muscle-induced mechanical load is necessary for proper bone formation in utero (Nowlan et al, 2007, 2008, 2010, 2012; Sharir et al, 2011).…”

Prenatal exposure to environmental factors and congenital limb defects

“…The morphological changes are well known, but the molecular controls are still being elucidated. The location of joints is presumably specified by specific HOX gene expression, particularly Hox11A, Hox11C, and Hox11D, that is required for proper joint formation (Koyama et al, 2010). The differentiation of the joint is first indicated by the expression of Wnt14, a factor necessary for joint development (Hartmann and Tabin, 2001;Garciadiego-C azares et al, 2004).…”