DF/HCC Program Affiliation

Cancer Cell Biology

Research Abstract

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. Heart Formation: We have found that heart tissue is induced in chick embryos by signals from the anterior endoderm. We have recently found that these cardiac inducing signals can be mimicked by a combination of BMP, FGF, Hedgehog and anti-Wnt signals, and are investigating if these same signals can induce cardiac tissue in either embryonal stem or mesenchymal stem cells. We are also trying to identify proteins that establish the competence of cells to interpret this combination of signals as cardiogenic. In addition, we are studying the transcriptional targets of the Mesp1 protein, a transcription factor implicated in the generation/migration of heart precursors. Skeletal muscle formation: Pax-3 and Pax-7 modulate both skeletal muscle generation in the embryo and the production of skeletal muscle stem cells, termed satellite cells, in the adult, respectively. We are studying the co-factors that control the activity of these Pax proteins, as well as the down-stream transcriptional targets of these proteins to understand how these transcription factors control the genesis of skeletal muscle precursor cells. In addition we are interested in understanding the signals that regulate satellite cell generation and expansion during skeletal muscle regeneration. 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. In addition, we have recently found that forced expression of either Sox9 or Nkx3.2 induces a competence state for Runx family transcription factors to induce chondrocyte maturation. We are studying how Sox9 and Nkx3.2 regulate the induction of chondrogenesis and how these factors work with Runx family transcription factors and various signaling molecules to regulate the process of cartilage maturation, endochondral ossification, and maintenance of articular cartilage. One goal of this work is to establish conditions to derive stem cells for articular cartilage, and to understand the parameters that control the proliferation and maintenance of articular cartilage.

Publications

• Lee KH, Evans S, Ruan TY, Lassar AB.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.
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• Tzahor E, Kempf H, Mootoosamy RC, Poon AC, Abzhanov A, Tabin CJ, Dietrich S, Lassar AB.Antagonists of Wnt and BMP signaling promote the formation of vertebrate head muscle.Genes Dev 2003 Dec 15;17(24):3087-99.
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• Zeng L, Kempf H, Murtaugh LC, Sato ME, Lassar AB.Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis.Genes Dev 2002 Aug 1;16(15):1990-2005.
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• Murtaugh LC, Zeng L, Chyung JH, Lassar AB.The chick transcriptional repressor Nkx3.2 acts downstream of Shh to promote BMP-dependent axial chondrogenesis.Dev Cell 2001 Sep;1(3):411-22.
  11702952
• Tzahor E, Lassar AB.Wnt signals from the neural tube block ectopic cardiogenesis.Genes Dev 2001 Feb 1;15(3):255-60.
  11159906
• Marvin MJ, Di Rocco G, Gardiner A, Bush SM, Lassar AB.Inhibition of Wnt activity induces heart formation from posterior mesoderm.Genes Dev 2001 Feb 1;15(3):316-27.
  11159912