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.
  15329343
• 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.
  14701876
• 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.
  12154128
• 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
• 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
• Tzahor E, Lassar AB.Wnt signals from the neural tube block ectopic cardiogenesis.Genes Dev 2001 Feb 1;15(3):255-60.
  11159906
• Kempf H, Ionescu A, Udager AM, Lassar AB.Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression.Dev Dyn 2007 Jul;236(7):1954-62.
  17576141
• Holowacz T, Zeng L, Lassar AB.Asymmetric localization of numb in the chick somite and the influence of myogenic signals.Dev Dyn 2006 Mar;235(3):633-45.
  16425215
• Provot S, Kempf H, Murtaugh LC, Chung UI, Kim DW, Chyung J, Kronenberg HM, Lassar AB.Nkx3.2/Bapx1 acts as a negative regulator of chondrocyte maturation.Development 2006 Feb;133(4):651-62.
  16421188
• Kim DW, Lassar AB.Smad-dependent recruitment of a histone deacetylase/Sin3A complex modulates the bone morphogenetic protein-dependent transcriptional repressor activity of Nkx3.2.Mol Cell Biol 2003 Dec;23(23):8704-17.
  14612411
• Kim DW, Kempf H, Chen RE, Lassar AB.Characterization of Nkx3.2 DNA binding specificity and its requirement for somitic chondrogenesis.J Biol Chem 2003 Jul 25;278(30):27532-9.
  12746429
• Stuckmann I, Evans S, Lassar AB.Erythropoietin and retinoic acid, secreted from the epicardium, are required for cardiac myocyte proliferation.Dev Biol 2003 Mar 15;255(2):334-49.
  12648494
• Lazaro JB, Bailey PJ, Lassar AB.Cyclin D-cdk4 activity modulates the subnuclear localization and interaction of MEF2 with SRC-family coactivators during skeletal muscle differentiation.Genes Dev 2002 Jul 15;16(14):1792-805.
  12130539
• Novitch BG, Spicer DB, Kim PS, Cheung WL, Lassar AB.pRb is required for MEF2-dependent gene expression as well as cell-cycle arrest during skeletal muscle differentiation.Curr Biol 1999 May 6;9(9):449-59.
  10322110
• Murtaugh LC, Chyung JH, Lassar AB.Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling.Genes Dev 1999 Jan 15;13(2):225-37.
  9925646
• Schultheiss TM, Lassar AB.Induction of chick cardiac myogenesis by bone morphogenetic proteins.Cold Spring Harb Symp Quant Biol 1997;62:413-9.
  9598376
• Reshef R, Maroto M, Lassar AB.Regulation of dorsal somitic cell fates: BMPs and Noggin control the timing and pattern of myogenic regulator expression.Genes Dev 1998 Feb 1;12(3):290-303.
  9450925
• Maroto M, Reshef R, Münsterberg AE, Koester S, Goulding M, Lassar AB.Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue.Cell 1997 Apr 4;89(1):139-48.
  9094722
• Schultheiss TM, Burch JB, Lassar AB.A role for bone morphogenetic proteins in the induction of cardiac myogenesis.Genes Dev 1997 Feb 15;11(4):451-62.
  9042859
• Skapek SX, Rhee J, Kim PS, Novitch BG, Lassar AB.Cyclin-mediated inhibition of muscle gene expression via a mechanism that is independent of pRB hyperphosphorylation.Mol Cell Biol 1996 Dec;16(12):7043-53.
  8943359
• Novitch BG, Mulligan GJ, Jacks T, Lassar AB.Skeletal muscle cells lacking the retinoblastoma protein display defects in muscle gene expression and accumulate in S and G2 phases of the cell cycle.J Cell Biol 1996 Oct;135(2):441-56.
  8896600
• Spicer DB, Rhee J, Cheung WL, Lassar AB.Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist.Science 1996 Jun 7;272(5267):1476-80.
  8633239
• Lassar AB, Münsterberg AE.The role of positive and negative signals in somite patterning.Curr Opin Neurobiol 1996 Feb;6(1):57-63.
  8794041
• Schultheiss TM, Xydas S, Lassar AB.Induction of avian cardiac myogenesis by anterior endoderm.Development 1995 Dec;121(12):4203-14.
  8575320
• Münsterberg AE, Kitajewski J, Bumcrot DA, McMahon AP, Lassar AB.Combinatorial signaling by Sonic hedgehog and Wnt family members induces myogenic bHLH gene expression in the somite.Genes Dev 1995 Dec 1;9(23):2911-22.
  7498788
• Lassar AB, Skapek SX, Novitch B.Regulatory mechanisms that coordinate skeletal muscle differentiation and cell cycle withdrawal.Curr Opin Cell Biol 1994 Dec;6(6):788-94.
  7880524
• Lassar AB, Davis RL, Wright WE, Kadesch T, Murre C, Voronova A, Baltimore D, Weintraub H.Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo.Cell 1991 Jul 26;66(2):305-15.
  1649701
• Lassar AB, Buskin JN, Lockshon D, Davis RL, Apone S, Hauschka SD, Weintraub H.MyoD is a sequence-specific DNA binding protein requiring a region of myc homology to bind to the muscle creatine kinase enhancer.Cell 1989 Sep 8;58(5):823-31.
  2550138
• Lassar AB, Thayer MJ, Overell RW, Weintraub H.Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1.Cell 1989 Aug 25;58(4):659-67.
  2548731
• Thayer MJ, Tapscott SJ, Davis RL, Wright WE, Lassar AB, Weintraub H.Positive autoregulation of the myogenic determination gene MyoD1.Cell 1989 Jul 28;58(2):241-8.
  2546677
• Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB, Miller AD.Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD.Proc Natl Acad Sci U S A 1989 Jul;86(14):5434-8.
  2748593
• Tapscott SJ, Davis RL, Thayer MJ, Cheng PF, Weintraub H, Lassar AB.MyoD1: a nuclear phosphoprotein requiring a Myc homology region to convert fibroblasts to myoblasts.Science 1988 Oct 21;242(4877):405-11.
  3175662
• Davis RL, Weintraub H, Lassar AB.Expression of a single transfected cDNA converts fibroblasts to myoblasts.Cell 1987 Dec 24;51(6):987-1000.
  3690668
• Lassar AB, Paterson BM, Weintraub H.Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts.Cell 1986 Dec 5;47(5):649-56.
  2430720