Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors

Abstract

The transcription factor Sox9 is expressed in all chondroprogenitors and has an essential role in chondrogenesis. Sox9 is also expressed in other tissues, including central nervous system, neural crest, intestine, pancreas, testis, and endocardial cushions, and plays a crucial role in cell proliferation and differentiation in several of these tissues. To determine the cell fate of Sox9-expressing cells during mouse embryogenesis, we generated mice in which a Cre recombinase gene preceded by an internal ribosome entry site was inserted into the 3 untranslated region of the Sox9 gene (Sox9-Cre knock-in). In the developing skeleton, Sox9 was expressed before Runx2, an early osteoblast marker gene. Cell fate mapping by using Sox9-Cre;ROSA26 reporter (R26R) mice revealed that Sox9-expressing limb bud mesenchymal cells gave rise to both chondrocytes and osteoblasts. Furthermore, a mutant in which the Osterix gene was inactivated in Sox9-expressing cells exhibited a lack of endochondral and intramembranous ossification and a lack of mature osteoblasts comparable with Osterix-null mutants. In addition, Sox9-expressing limb bud mesenchymal cells also contributed to tendon and synovium formation. By using Sox9-Cre;R26R mice, we also were able to systematically follow Sox9-expressing cells from embryonic day 8.0 to 17.0. Our results showed that Sox9-expressing cells contributed to the formation of all cell types of the spinal cord, epithelium of the intestine, pancreas, and mesenchyme of the testis. Thus, our results strongly suggest that all osteo-chondroprogenitor cells, as well as progenitors in a variety of tissues, are derived from Sox9-expressing precursors during mouse embryogenesis.imb skeleton is formed as a cartilage model that undergoes endochondral bone formation. At the initiation of limb development, undifferentiated mesenchymal cells in the lateral plate mesoderm receive proliferation signals from the apical ectodermal ridge. These cells start to aggregate and form mesenchymal condensations, which are the primordia of the limb skeleton, then differentiate into chondrocytes and generate a cartilage skeleton. Cells surrounding the nascent cartilage form the perichondrium and periosteum, specialized structures consisting of thin layers of mesenchymal cells. The cells surrounding the zone of hypertrophic chondrocytes begin to differentiate into osteoblasts and, together with blood vessels and osteoclasts, invade the mineralized cartilage matrix and replace cartilage by bone.Specific transcription factors regulate the differentiation pathways of chondrocytes and osteoblasts. Sox9, a transcription factor with a high-mobility group DNA-binding domain, activates chondrocyte-specific marker genes, such as Col2a1, Col11a2, and Aggrecan (1-3). Sox9 is expressed in all chondroprogenitors and chondrocytes except hypertrophic chondrocytes (4, 5). Campomelic dysplasia, a human disease that is caused by heterozygous mutations in the Sox9 gene, is characterized by a general hypoplasia of endochondral bones (6, 7). We have re...

Pancreas organogenesis: From bud to plexus to gland

“…This role is similar to its function in the hair bulge, intestinal epithelium, and neural crest (Cheung and Briscoe, 2003;Blache et al, 2004;Vidal et al, 2005). Sox9 expression is first detected at $E10.5 in the early pancreatic MPC, and lineage tracing revealed that the ''first-wave'' Sox9 þ progenitors, like Pdx1 þ and Ptf1a þ progenitors, produce cells of all three pancreatic lineages (Akiyama et al, 2005). Sox9 expression persists in the endocrine/duct bipotent progenitor pool located in the central epithelial cords of the maturing epithelial arbor during the secondary transition (Seymour et al, 2007;Lynn et al, 2007).…”

SOX9 determines RUNX2 transactivity by directing intracellular degradation

“…In the skeleton, SOX9 expression precedes RUNX2, and subsequently, SOX9 expression is maintained during the whole process of bone formation, from chondrocytes to osteoblasts. (47) The coordination between SOX9 and RUNX2 is highly important for the determination of MSC fate. It has been shown previously that SOX9 is able to exert a dominant inhibitory effect on RUNX2 function (32) ; however, the precise mechanisms involved are unclear.…”

Mechanisms of digit formation: Human malformation syndromes tell the story

“…This process requires the initial specification of precartilaginous cells (chondroprogenitors), which are not yet fully committed toward the cartilage lineage, and the following determination of a subset of these cells to form the definite cartilaginous condensation (Akiyama et al, 2005). The limb mesenchyme appears to have an intrinsic chondrogenic potential as a default fate, as can be seen in mesenchymal micromass cultures (see e.g., DeLise et al, 2000).…”

“…Sox9 directly regulates the expression of Col2a1 (Lefebvre et al, 1997;Ng et al, 1997). However, the expression of Sox9 alone is not sufficient for definitive determination of the chondrogenic cell fate, because cells expressing Sox9 in vivo can still adopt other cell fates (Akiyama et al, 2005). Heterozygous mutations in SOX9 cause campomelic dysplasia, a generalized lethal chondrodysplasia with sex reversal (Wagner et al, 1994).…”