Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors

TLDR

Sox9 is a transcription factor expressed in all chondroprogenitors and many other tissues, where it is essential for chondrogenesis, cell proliferation, and differentiation, and is present in the developing skeleton before the osteoblast marker Runx2. The study aimed to trace the fate of Sox9‑expressing cells during mouse embryogenesis by generating a Sox9‑Cre knock‑in mouse. Using Sox9‑Cre;R26R reporter mice, the authors lineage‑traced Sox9‑expressing cells from embryonic day 8.0 to 17.0 to follow their differentiation trajectories. Lineage tracing revealed that Sox9‑expressing limb‑bud mesenchymal cells differentiate into chondrocytes, osteoblasts, tendon, and synovium, and that Sox9‑derived cells also contribute to the spinal cord, intestinal epithelium, pancreas, and testis mesenchyme; loss of Osterix in these cells abolishes ossification, confirming that all osteo‑chondroprogenitor and many other progenitors arise 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.