Connective tissue is an irreplaceable component of the musculoskeletal system; however it has attracted far less attention than other tissue types. Odd-skipped is a drosophila pair-rule gene involved in embryonic segmentation. In mammals, two odd-skipped paralogs exist, Osr1 and Osr2. Odd-skipped genes encode zinc-finger transcription factors expressed in several organs of the developing embryo. For Osr1, functions in heart and kidney development have been described, while Osr2 has been linked to secondary palate formation and tooth development. We have analysed the expression of Osr1 and Osr2 in the chick limb and found both genes to be highly specific for irregular connective tissue. We have recently shown that Osr1 and Osr2 are both involved in the differentiation of irregular connective tissue fibroblasts and are potent inhibitors of mesenchymal differentiation along other cell lineages (Stricker et al. 2012).
A global analysis of Osr1 target genes in comparison to other connective tissue-expressed transcription factors via combining RNA-Sequencing and ChIP-Sequencing highlighted paracrine signalling molecules as well as extracellular matrix molecules as pivotal downstream targets. Intriguingly, different transcription factors from different connective tissue sub-types showed a remarkable overlap in extracellular matrix-related gene expression, defining a core connective tissue signature. Each transcription factor, on the other hand, regulated specific matrix targets, indicating a transcription factor-based matrix code during limb development, instructive for tissue patterning (Orgeur et al. 2018).
Going from chicken to mouse as model system we found a conserved expression pattern of Osr1 in muscle connective tissue during limb development. Loss of Osr1 function impaired connective tissue-mediated limb muscle patterning. This involved an altered expression of extracellular matrix molecules, which we assume to play a key role in instructing myogenic progenitors and maintaining the myogenic pool.
Furthermore we showed that Osr1-expressing mesenchymal cells in the embryonic limb bud are a developmental source of the so-called fibro-adipogenic progenitors, FAPs, an adult muscle-resident mesenchymal stem cell-like population (Vallecillo-Garcia et al. 2017).
Adult muscle-resident mouse FAPs do not express Osr1, as opposed to their developmental counterparts. Intriguingly, upon acute injury, FAPs re-activate Osr1 expression, making Osr1 a suitable marker for FAPs during muscle injury regeneration (Stumm et al. 2018). At present we analyse the function of Osr1 in adult FAPs during muscle regeneration.
This project is a part of the international graduate school for Myology, “MyoGrad”