Current work in my lab focuses on the signals and transcription factors that maintain skeletal muscle stem cells, the transcriptional regulatory pathways that regulates chondrocyte formation and maturation, and the development of a gene therapy model to treat osteoarthritis:
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 to induce myogenesis. 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 where immature chondrocytes undergo maturation, hypertrophy and apopotosis and are replacement by bone tissue; a process termed endochondral ossification. In contrast articular chondrocytes remain immature and do not normally undergo endochondral ossification. We are studying how the initial cartilage template is induced and are trying to elucidate how chondrocytes “decide” whether to undergo maturation which leads to endochondral ossification or remain immature, as in the articular cartilage of our joints. The induction of chondrogenesis in the embryo is regionally controlled by the combination of Shh, Wnt, FGF, and BMP signals. We are studying how these signaling molecules regulate the expression of the prochondogenic transcription factor Sox9 by controlling the epigenetic landscape of this locus, 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. 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.
Developing a gene therapy model for osteoarthritis: The degeneration of articular cartilage is a hallmark of osteoarthritis, which stereotypically progresses from the superficial layer into the deeper layers of the articular cartilage. We have recently developed a mouse line capable of driving Cre-induced gene expression in the superficial layer of articular cartilage and are utilizing this strain of mice to investigate the therapeutic potential of various secreted proteins to block the progression of osteoarthritis in murine models of this disease. Lastly, we are studying whether transcription factors that are known to be involved in promoting chondrocyte maturation and hypertrophy play a role in the progression of osteoarthritis.
Tzahor E, Kempf H, Mootoosamy RC, Poon AC, Abzhanov A, Tabin CJ, Dietrich S, and Lassar AB. (2003). Antagonists of Wnt and BMP signaling promote the formation of vertebrate head muscle. Genes Dev. Dec 15;17(24):3087-3099.
Lee KH, Evans S, Ruan TY, Lassar AB. (2004) SMAD-mediated modulation of YY1 activity regulates the BMP response and cardiac-specific expression of a GATA4/5/6-dependent chick Nkx2.5 enhancer. Development. 2004 Oct;131(19):4709-23.
Tamara Holowacz, Li Zeng, Andrew B. Lassar (2006). Asymmetric localization of Numb in the chick somite and the influence of myogenic signals. Developmental Dynamics 235(3):633-45.
Sylvain Provot, Hervé Kempf, L. Charles Murtaugh, Ung-il Chung, Dae-Won Kim, Jay Chyung, Henry M. Kronenberg and Andrew B. Lassar (2006). Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation. Development. 133, 651-662.
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.
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. 2008. 323(2):152-65. PMID: 18796301.
Kumar D, Shadrach JL, Wagers AJ, Lassar AB. (2009) Id3 Is a Direct Transcriptional Target of Pax7 in Quiescent Satellite Cells. Mol Biol Cell. 20(14):3170-7.PMID: 19458195.
Kumar D, Lassar AB. (2009) The transcriptional activity of Sox9 in chondrocytes is regulated by RhoA signaling and actin polymerization. Mol Cell Biol. 29(15):4262-73. PMID: 19470758
Kozhemyakina E, Cohen T, Yao TP, Lassar AB. (2009) PTHrP represses chondrocyte hypertrophy through a PP2A/HDAC4/MEF2 pathway. Mol Cell Biol. 2009 Nov;29(21):5751-62. PMID: 19704004
Lassar AB. (2009) The p38 MAPK family, a pushmi-pullyu of skeletal muscle differentiation. J Cell Biol. 2009 Dec 28;187(7):941-3. Epub 2009 Dec 21.PMID: 20026653