Abstract
During limb development, posterior Hox genes of the Hoxa- and Hoxd cluster provide positional information along the limb axis. Here we report a new function for Hoxa11 and Hoxd11 in regulating the early steps of chondrocyte differentiation. We analyzed forelimbs of Hoxa11−/−;d11−/− and Ulnaless mice, which are characterized by specifically shortened zeugopods. By detailed morphological and molecular analyses, we show that loss of Hoxa11 and Hoxd11 in the ulna of both mutants leads to an arrest of chondrocyte differentiation at a step before the separation into round and columnar cells takes place. Furthermore, we demonstrate that Hoxa11 and Hoxd11 act upstream of Runx2 and Shox2, two key regulators of chondrocyte differentiation. We hypothesize that Runx2 activates Shox2 in early chondrocytes, which at later stages induces Runx2 expression to regulate hypertrophic differentiation. These results give insight into mechanisms by which positional information might be translated into a specific bone pattern.
Highlights
The long bones of vertebrates are formed by the process of endochondral ossification, during which a cartilage intermediate is established and subsequently replaced by bone [1,2,3]
To gain insight into the molecular mechanisms acting downstream of Hox genes in chondrocytes, we investigated the process of chondrocyte differentiation in Hoxa112/2;d112/2 mice at different developmental stages in detail and compared it to that of Ulnaless mutants
In the radius hypertrophic differentiation is delayed at both stages, but a few columnar chondrocytes can be detected in the anterior curve at E16.5 (Fig. 1H)
Summary
The long bones of vertebrates are formed by the process of endochondral ossification, during which a cartilage intermediate is established and subsequently replaced by bone [1,2,3]. Endochondral ossification is initiated by mesenchymal cells that condense and differentiate into chondrocytes, which form the cartilage anlagen of the future skeletal elements. In the center of the cartilage anlagen, the cells start to successively differentiate into several types of chondrocytes, each showing a characteristic cell shape. The proliferating chondrocytes separate into two cell types: round, low-proliferating chondrocytes at the distal end of the skeletal element and columnar, highproliferating chondrocytes in the center [4,5]. In parallel with hypertrophic differentiation, cells of the perichondrium differentiate into osteoblasts forming the periosteum. Blood vessels invade the hypertrophic region providing osteoblasts and osteoclasts to replace the cartilage by bone [1,2,3]
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