Die Funktion von Trps1 in der Differenzierung endochondraler Knochen
Final Report Abstract
Trps1, the gene mutated in human Tricho-Rhino-Phalangeal Syndrome, represents an atypical member of the GATA-family of transcription factors. Here we have analyzed the role of Trps1 during endochondral ossification and found that it regulates at least three steps of chondrocyte development: it regulates the proliferation rate, the expansion of the pool of round low proliferating chondrocytes at the ends of the cartilage elements and the transition of proliferating into hypertrophic chondrocytes. We further found that Trps1 interacts with Indian hedgehog (Ihh)/Gli3 signaling thereby regulating chondrocyte differentiation and proliferation. We demonstrate that Trps1 specifically binds to the activator form of Gli3 in vitro and in vivo, whereas the repressor form of Gli3 does not interact with Trps1. A domain of aa within Trps1, containing three predicted zinc finger motifs, is sufficient for the interaction with Gli3. Using different mouse models we show that in round, low proliferating chondrocytes Trps1 and the repressor activity of Gli3 are required to expand this pool of cells and to locate the expression domain of Parathyroid hormone related peptide (PTHrP). In columnar, proliferating chondrocytes Trps1 and Ihh/Gli3 have an activating function, which seems to be translated in parallel pathways. The differentiation of columnar and hypertrophic chondrocytes is supported by Trps1 independent of Gli3. As in parallel studies it was shown that Trps1 interacts with other transcription factors, like Runx2 in hypertrophic chondrocytes, we postulate that Trps1 interacts with different subsets of co-factors in distinct cell types.
Publications
- (2005). Gli3 has repressing and activating functions downstream of Ihh in regulating two distinct steps of chondrocyte differentiation. Development 132, 5249-60
Koziel, L., Wuelling, M., Schneider, S., Vortkamp, A.
- (2008). Tricho-rhino-phalangeal syndrome with supernumerary teeth. J Dent Res. 87:1027-31
Kantaputra P, Miletich I, Lüdecke HJ, Suzuki EY, Praphanphoj V, Shivdasani R, Wuelling M, Vortkamp A, Napierala D, Sharpe PT
- (2009). Trps1, a regulator of chondrocyte proliferation and differentiation, interacts with the activator form of Gli3. Dev. Biol 328, 40-53. [Epub 2009 Jan 14]
Wuelling, M., Kaiser, F. J., Buelens, L. A., Braunholz, D., Shivdasani, R. A., Depping, R. and Vortkamp, A.
- (2010). Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification. Pediatr Nephrol. 25, 625-31. [Epub 2009 Dec 1]
Wuelling M, Vortkamp A
