Photo of Andrew B. Lassar,   Ph.D.

Andrew B. Lassar, Ph.D.

Harvard Medical School

Harvard Medical School
Phone: (617) 432-3831
Fax: (617) 738-0516

Andrew B. Lassar, Ph.D.

Harvard Medical School


  • Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School


Research Abstract

Current work in my lab focuses on the transcriptional regulatory pathways that regulate chondrocyte formation and maturation, elucidation of how mechanical loading regulates gene expression in the joint, identification of target proteins to block progression of osteoarthritis, and the regulation of DNA methylation by Wnt and FGF signals.

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 both identifying new transcription factors that control chondrocyte maturation and studying how the activity of these transcription factors are regulated by signaling molecules. Finally, we have recently identified a stem cell population for articular cartilage and are trying to elucidate the parameters that control the proliferation and maintenance of the articular cartilage.

Regulation of gene expression by mechano-signaling: Lubricin, is a secreted proteoglycan encoded by the Prg4 locus, that is abundantly expressed by superficial zone articular chondrocytes and has been noted to be both sensitive to mechanical loading and to protect against the development of osteoarthritis. We have recently demonstrated that Fluid Flow Shear Stress (FFSS) increases secretion of extracellular PGE2, PTHrP and ATP (by epiphyseal chondrocytes) which together engage both PKA and Ca++ regulated signaling pathways, that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and Fluid Flow Shear Stress both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by Fluid Flow Shear Stress that promote CREB-dependent gene expression in this tissue.

Regulation of DNA methylation by Wnt and FGF signals: The formation of cartilage is restricted to the core of the limb bud mesenchyme by ectodermal Wnts, which can irreversibly silence expression of the prochondrogenic transcription factor Sox9. In contrast, fibroblast growth factor (FGF) signals from the apical ectodermal ridge maintain the competence of chondrogenic precursors to undergo chondrogenesis once these cells go out of range of ectodermal Wnt signals. We have found that Wnt signals induce both a repressive chromatin mark (H3K27me3) and DNA methylation over the Sox9 promoter and that Wnt-induced irreversible silencing of the Sox9 gene requires DNA methylation of this locus, which is specifically countered by FGF signals. We are studying how these two crucial signaling pathways antagonistically regulate DNA methylation of both Sox9 and other loci during development.



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  • Kozhemyakina E, Lassar AB, Zelzer E. A pathway to bone: signaling molecules and transcription factors involved in chondrocyte development and maturation. Development 2015; 142:817-831. PubMed
  • Kozhemyakina E, Zhang M, Ionescu A, Ayturk UM, Ono N, Kobayashi A, Kronenberg H, Warman ML, Lassar AB. Identification of a Prg4-positive articular cartilage progenitor cell population. 2015. PubMed
  • Daoud G, Kempf H, Kumar D, Kozhemyakina E, Holowacz T, Kim DW, Ionescu A, Lassar AB. BMP-mediated induction of GATA4/5/6 blocks somitic responsiveness to SHH. Development 2014; 141:3978-87. PubMed
  • Kumar D, Lassar AB. Fibroblast Growth Factor Maintains Chondrogenic Potential of Limb Bud Mesenchymal Cells by Modulating DNMT3A Recruitment. Cell Rep 2014; 8:1419-31. PubMed
  • Ogawa H, Kozhemyakina E, Hung HH, Grodzinsky AJ, Lassar AB. Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways. Genes Dev 2014; 28:127-39. PubMed
  • Kozhemyakina E, Ionescu A, Lassar AB. GATA6 is a crucial regulator of Shh in the limb bud. PLoS Genet. 2014; 10:e1004072. PubMed
  • Clark CD, Zhang B, Lee B, Evans SI, Lassar AB, Lee KH. Evolutionary Conservation of Nkx2.5 Autoregulation in the Second Heart Field. Dev Biol 2012. PubMed
  • Ionescu A, Kozhemyakina E, Nicolae C, Kaestner KH, Olsen BR, Lassar AB. FoxA family members are crucial regulators of the hypertrophic chondrocyte differentiation program. Dev Cell 2012; 22:927-39. PubMed
  • Kamei CN, Kempf H, Yelin R, Daoud G, James RG, Lassar AB, Tabin CJ, Schultheiss TM. Promotion of avian endothelial cell differentiation by GATA transcription factors. Dev Biol 2011. PubMed
  • Lassar AB. The p38 MAPK family, a pushmi-pullyu of skeletal muscle differentiation. J Cell Biol 2009; 187:941-3. PubMed
  • Kozhemyakina E, Cohen T, Yao TP, Lassar AB. Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway. Mol Cell Biol 2009; 29:5751-62. PubMed
  • Kumar D,Lassar AB. The transcriptional activity of Sox9 in chondrocytes is regulated by RhoA signaling and actin polymerization. Mol Cell Biol 2009; 29:4262-73. PubMed
  • Kumar D,Shadrach JL,Wagers AJ,Lassar AB. Id3 Is a Direct Transcriptional Target of Pax7 in Quiescent Satellite Cells. Mol Biol Cell 2009. PubMed
  • Cairns DM,Sato ME,Lee PG,Lassar AB,Zeng L. A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Dev Biol 2008; 323:152-65. PubMed
  • Kempf H, Ionescu A, Udager AM, Lassar AB. Prochondrogenic signals induce a competence for Runx2 to activate hypertrophic chondrocyte gene expression. Dev Dyn 2007; 236:1954-62. PubMed
  • Holowacz T, Zeng L, Lassar AB. Asymmetric localization of numb in the chick somite and the influence of myogenic signals. Dev Dyn 2006; 235:633-45. PubMed
  • 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; 133:651-62. PubMed
  • 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; 131:4709-23. PubMed
  • 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 2004; 17:3087-99. PubMed
  • 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; 23:8704-17. PubMed
  • 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; 278:27532-9. PubMed
  • Stuckmann I, Evans S, Lassar AB. Erythropoietin and retinoic acid, secreted from the epicardium, are required for cardiac myocyte proliferation. Dev Biol 2003; 255:334-49. PubMed
  • 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; 16:1990-2005. PubMed
  • 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; 16:1792-805. PubMed
  • 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; 1:411-22. PubMed
  • Marvin MJ, Di Rocco G, Gardiner A, Bush SM, Lassar AB. Inhibition of Wnt activity induces heart formation from posterior mesoderm. Genes Dev 2001; 15:316-27. PubMed
  • Tzahor E, Lassar AB. Wnt signals from the neural tube block ectopic cardiogenesis. Genes Dev 2001; 15:255-60. PubMed
  • 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; 9:449-59. PubMed
  • Murtaugh LC, Chyung JH, Lassar AB. Sonic hedgehog promotes somitic chondrogenesis by altering the cellular response to BMP signaling. Genes Dev 1999; 13:225-37. PubMed
  • 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; 12:290-303. PubMed
  • Maroto M, Reshef R, M. Ectopic Pax-3 activates MyoD and Myf-5 expression in embryonic mesoderm and neural tissue. Cell 1997; 89:139-48. PubMed
  • Schultheiss TM, Burch JB, Lassar AB. A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes Dev 1997; 11:451-62. PubMed
  • Schultheiss TM, Lassar AB. Induction of chick cardiac myogenesis by bone morphogenetic proteins. Cold Spring Harb Symp Quant Biol 1998; 62:413-9. PubMed
  • 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; 16:7043-53. PubMed
  • 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; 135:441-56. PubMed
  • Spicer DB, Rhee J, Cheung WL, Lassar AB. Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist. Science 1996; 272:1476-80. PubMed
  • Lassar AB, M. The role of positive and negative signals in somite patterning. Curr Opin Neurobiol 1996; 6:57-63. PubMed
  • M. Combinatorial signaling by Sonic hedgehog and Wnt family members induces myogenic bHLH gene expression in the somite. Genes Dev 1995; 9:2911-22. PubMed
  • Schultheiss TM, Xydas S, Lassar AB. Induction of avian cardiac myogenesis by anterior endoderm. Development 1995; 121:4203-14. PubMed
  • Lassar AB, Skapek SX, Novitch B. Regulatory mechanisms that coordinate skeletal muscle differentiation and cell cycle withdrawal. Curr Opin Cell Biol 1994; 6:788-94. PubMed
  • 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; 66:305-15. PubMed
  • 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; 58:823-31. PubMed
  • Lassar AB, Thayer MJ, Overell RW, Weintraub H. Transformation by activated ras or fos prevents myogenesis by inhibiting expression of MyoD1. Cell 1989; 58:659-67. PubMed
  • Thayer MJ, Tapscott SJ, Davis RL, Wright WE, Lassar AB, Weintraub H. Positive autoregulation of the myogenic determination gene MyoD1. Cell 1989; 58:241-8. PubMed
  • 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; 86:5434-8. PubMed
  • 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; 242:405-11. PubMed
  • Davis RL, Weintraub H, Lassar AB. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 1987; 51:987-1000. PubMed
  • Lassar AB, Paterson BM, Weintraub H. Transfection of a DNA locus that mediates the conversion of 10T1/2 fibroblasts to myoblasts. Cell 1986; 47:649-56. PubMed