The various projects in my lab seek to elucidate the molecular circuitry that regulates mesodermal cell fate determination during vertebrate development and recruitment of stem cells in the adult.
Skeletal muscle formation and regeneration: Pax3 and Pax7 are closely related transcription factors that are essential for both skeletal muscle generation in the embryo and the production of skeletal muscle stem cells, termed satellite cells, in the adult. In the context of skeletal muscle stem cells, Pax3 and Pax7 activate the expression of the MyoD family, which are key transcriptional regulators of skeletal muscle development. We are studying the signaling pathways and the transcriptional co-factors that control the activity of these Pax proteins. In addition, we are studying the down-stream transcriptional targets of these proteins (in addition to the MyoD family) to understand how these transcription factors control the genesis of skeletal muscle stem cells. Lastly, we are studying the signals that regulate satellite cell generation and expansion during skeletal muscle regeneration and growth.
Chondrogenesis: Most of the bony tissue in vertebrates is initially molded upon a cartilage template which undergoes a stereotypic maturation process and replacement by bone tissue; a process termed endochondral ossification. We are studying how the initial cartilage template is induced and modeled. We have found that Hedgehog signaling induces a competence in paraxial mesodermal precursor cells (termed somites) for subsequent BMP signals to activate chondrogenesis, and that this chondrogenic competence is mediated by the induction of both Sox9 and Nkx3.2, two pro-chondrogenic transcription factors. The induction of chondrogenesis in the embryo is regionally controlled by Shh, Wnt, FGF, and BMP signals. We are how these signaling molecules regulate the expression of Sox9, how cell shape and the polymerization state of the actin cytoskeleton controls chondrocyte induction and Sox9 gene expression, and the transcriptional circuits that regulate the process of cartilage maturation, endochondral ossification, and maintenance of articular cartilage. In addition, we are studying how the activity of transcription factors that play a crucial role in chondrocyte maturation are regulated by signaling molecules, such as Parathyroid Hormone related Peptide (PTHrP) that regulate chondrocyte maturation during development. Future work will focus on evaluating whether the activity of these transcription factors is altered in experimental models of osteoarthritis. Finally, we are trying to determine whether a stem cell population exists for articular cartilage and are trying to elucidate the parameters that control the proliferation and maintenance of articular cartilage.
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References:
- Hervé Kempf, Andreia Ionescu, Aaron M. Udager, and Andrew B. Lassar (2007). Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression. Developmental Dynamics, 236:1954–1962.
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Cairns DM, Sato ME, Lee PG, Lassar AB, Zeng L. (2008) A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Dev Biol. 323(2):152-65.
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Kumar D, Shadrach JL, Wagers AJ, Lassar AB. (2009) Id3 Is a Direct Transcriptional Target of Pax7 in Quiescent Satellite Cells. Mol Biol Cell. 2009 May 20. In press
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Kumar D, Lassar AB. (2009) The transcriptional activity of Sox9 in chondrocytes is regulated by RhoA signaling and actin polymerization. Mol Cell Biol. 2009 May 26. In press
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