Stanislav Y. Shvartsman
Carl Icahn Lab, 248
Lab (609) 258-7071
Karen M. Oliver
Quantitative Analysis of Development
The main focus of our laboratory is on the quantitative analysis of development. Our goal is to establish truly predictive and multiscale models that connect multiple levels of description, from gene sequence to pattern formation and morphogenesis. We emphasize close coupling between experiments, computations, and theory, and use Drosophila as an experimental system for model validation. Current projects include genome-wide experimental analysis of signal integration in the Drosophila ovary, computational prediction of sequence-specific patterns of gene regulation by multiple extracellular signals, parameter estimation for morphogen gradients, and quantitative analysis of feedback control in pattern formation.
Signaling crosstalk in the drosophila ovary
The dorsoventral patterning of the follicular epithelium in the developing Drosophila egg relies on the joint activity of evolutionarily conserved EGF and BMP signaling pathways. We have carried out a genome-wide screen for common targets of EGF and BMP pathways in the ovary, established the spatial patterns of their expression, and begun to probe the mechanisms for their transcriptional and posttranscriptional regulation. The current challenge is to go beyond simple association of extracellular signals and transcriptional targets and to understand how the spatial patterns of identified genes are established by integration of two extracellular signals.
Quantitative analysis of morphogen gradients
Pattern formation in development depends on quantitative control of the spatial ranges of secreted ligands. At this time, direct measurements of the length scales of morphogen ligands are extremely difficult. We have developed a parameter estimation approach for quantifying the spatial range of Gurken, an EGF-like ligand that acts as a morphogen in patterning of the Drosophila egg. Our approach combines transport modeling and quantitative characterization of targeted gene expression systems in oogenesis. Using this method, we have estimated the magnitude of a dimensionless parameter that controls the Gurken gradient. We are currently extending this approach to analyze the terminal patterning system in the early embryo.
Negative feedback in pattern formation systems
Negative feedbacks are abundant in patterning networks, but both the biochemical basis of feedbacks and their functional significance are poorly understood at this time. Recent experiments in the Lemmon laboratory at UPenn have provided a detailed biochemical characterization of the biochemical action of Argos, an extracellular inhibitor that provides negative feedback for EGFR signaling in Drosophila. We are using this information to understand the mechanism of Argos action in the embryonic ventral ectoderm (VE). We are interested in determining both the spatial range of Argos and its contribution to the robustness in VE patterning.
Berezhkovskii AM, Shvartsman SY. (2015) Dynamics of gradient formation by intracellular shuttling. J Chem Phys.143(7):074116. Pubmed
Jindal GA, Goyal Y, Burdine RD, Rauen KA, Shvartsman SY. (2015) RASopathies: unraveling mechanisms with animal models. Dis Model Mech. 8(8):769-82. Pubmed
Murisic N, Hakim V, Kevrekidis IG, Shvartsman SY, Audoly B. (2015) From discrete to continuum models of three-dimensional deformations in epithelial sheets. Biophys J. 109(1): 154-63. Pubmed
Futran AS, Kyin S, Shvartsman SY, Link AJ. (2015) Mapping the binding interface of ERK and transcriptional repressor Capicua using photocrosslinking. Proc Natl Acad Sci U S A. [Epub ahead of print]
Osterfield M, Schüpbach T, Wieschaus E, Shvartsman SY. (2015) Diversity of epithelial morphogenesis during eggshell formation in drosophilids. Development. 142: 1971-7. Pubmed
Dsilva CJ, Lim B, Lu H, Singer A, Kevrekidis IG, Shvartsman SY. (2015) Temporal ordering and registration of images in studies of developmental dynamics. Development. 142:1717-24. Pubmed
Charbonnier E, Fuchs A, Cheung LS,...Shvartsman SY, Pyrowolakis G. (2015) BMP-dependent gene repression cascade in Drosophila eggshell patterning. Dev Biol. 400:258-65. Pubmed
Fletcher AG, Osterfield M, Baker RE, Shvartsman SY. (2014) Vertex models of epithelial morphogenesis. Biophys J. 106: 2291-304. Pubmed
Berezhkovskii AM, Shvartsman SY. (2014) On the GFP-based analysis of dynamic concentration profiles. Biophys J. 106: L13-15. Pubmed
Futran AS, Link AJ, Seger R, Shvartsman SY. (2013) ERK as a model for systems biology of enzyme kinetics in cells. Curr Biol. 23: R972-79. Pubmed
Cheung LS, Simakov DS, Fuchs A, Pyrowolakis G, Shvartsman SY. (2013) Dynamic model for the coordination of two enhancers of broad by EGFR signaling. Proc Natl Acad Sci. 110: 17939-44. Pubmed
Kim Y, Iagovitina A, Ishihara K,...Shvartsman SY. (2013) Context-dependent transcriptional interpretation of mitogen activated protein kinase signaling in the Drosophila embryo. Chaos. 23: 025105. Pubmed
Lim B, Samper N, Lu H, Rushlow C, Jiménez G, Shvartsman SY. (2013) Kinetics of gene derepression by ERK signaling. Proc Natl Acad Sci. 110: 10330-35. Pubmed
Osterfield M, Du X, Schüpbach T, Wieschaus E, Shvartsman SY. (2013) Three-dimensional epithelial morphogenesis in the developing Drosophila egg. Dev Cell. 24: 400-10. Pubmed
Shvartsman SY, Baker RE. (2012) Mathematical models of morphogen gradients and their effects on gene expression. Wiley Interdiscip Rev Dev Biol. 1: 715-30. Pubmed
Grimm O, Zini VS, Kim Y, Casanova J, Shvartsman SY, Wieschaus E. (2012) Torso RTK controls Capicua degradation by changing its subcellular localization. Development. 139: 3962-3968. Pubmed
Kanodia JS, Liang HL, Kim Y,...Shvartsman SY. (2012) Pattern formation by graded and uniform signals in the early Drosophila embryo. Biophys J. 102: 427-33. PubMed
Cheung LS, Schüpbach T, Shvartsman SY. (2011) Pattern formation by receptor tyrosine kinases: analysis of the Gurken gradient in Drosophila oogenesis. Curr Opin Genet Dev. 21: 719-25. PubMed
Zartman JJ, Cheung LS, Niepielko MG,...Shvartsman SY. (2011) Pattern formation by a moving morphogen source. Phys Biol. 8: 045003. PubMed
Kim Y, Andreu MJ, Lim B,...Shvartsman SY. (2011) Gene regulation by MAPK substrate competition. Dev Cell. 20: 880-87. PubMed
Kim Y, Paroush Z, Nairz K, Hafen E, Jiménez G, Shvartsman SY. (2011) Substrate-dependent control of MAPK phosphorylation in vivo. Mol Syst Biol. 7: 467. PubMed
Sample C, Shvartsman SY. (2010) Multiscale modeling of diffusion in the early Drosophila embryo. Proc Natl Acad Sci. 107: 10092-96. PubMed
Kim Y, Coppey M, Grossman R,...Shvartsman SY. (2010) MAPK substrate competition integrates patterning signals in the Drosophila embryo. Curr Biol. 20: 446-51. PubMed
Kanodia JS, Rikhy R, Kim Y,...Shvartsman SY. (2009) Dynamics of the Dorsal morphogen gradient. Proc Natl Acad Sci. 106: 21707-12. PubMed
Zartman JJ, Kanodia JS, Cheung LS, Shvartsman SY. (2009) Feedback control of the EGFR signaling gradient: superposition of domain-splitting events in Drosophila oogenesis. Development. 136: 2903-11. PubMed
Lembong J, Yakoby N, Shvartsman SY. (2009) Pattern formation by dynamically interacting network motifs. Proc Natl Acad Sci. 106: 3213-18. PubMed
Shvartsman SY, Coppey M, Berezhkovskii AM. (2009) MAPK signaling in equations and embryos. Fly. 3: 62-67 PubMed
Yakoby N, Bristow CA, Gong D,...Shvartsman SY. (2008) A combinatorial code for pattern formation in Drosophila oogenesis. Dev Cell. 15: 725-37. PubMed
Zartman JJ, Kanodia JS, Yakoby N,...Shvartsman SY. (2008) Expression patterns of cadherin genes in Drosophila oogenesis. Gene Expr Patterns. 9: 31-36. PubMed
Lembong J, Yakoby N, Shvartsman SY. (2008) Spatial regulation of BMP signaling by patterned receptor expression. Tissue Eng Part A. 14: 1469-77. PubMed
Zartman JJ, Yakoby N, Bristow CA,...Shvartsman SY. (2008) Cad74A is regulated by BR and is required for robust dorsal appendage formation in Drosophila oogenesis. Dev Biol. 322: 289-301. PubMed
Shvartsman SY, Coppey M, Berezhkovskii AM. (2008) Dynamics of maternal morphogen gradients in Drosophila. Curr Opin Genet Dev. 18: 342-47. PubMed
Coppey M, Boettiger AN, Berezhkovskii AM, Shvartsman SY. (2008) Nuclear trapping shapes the terminal gradient in the Drosophila embryo. Curr Biol. 18: 915-19. PubMed
Yakoby N, Lembong J, Schüpbach T, Shvartsman SY. (2008) Drosophila eggshell is patterned by sequential action of feedforward and feedback loops. Development. 135: 343-51. PubMed
Zartman JJ, Shvartsman SY. (2007) Enhancer organization: transistor with a twist or something in a different vein? Curr Biol. 17: R1048-50. PubMed
Coppey M, Berezhkovskii AM, Kim Y, Boettiger AN, Shvartsman SY. (2007) Modeling the bicoid gradient: Diffusion and reversible nuclear trapping of a stable protein. Dev Biol. 312: 623-30. PubMed
Qiao L, Nachbar RB, Kevrekidis IG, Shvartsman SY. (2007) Bistability and oscillations in the Huang-Ferrell model of MAPK signaling. PLoS Comput Biol. 3: 1819-26. PubMed
Coppey M, Berezhkovskii AM, Sealfon SC, Shvartsman SY. (2007) Time and length scales of autocrine signals in three dimensions. Biophys J. 93: 1917-22. PubMed
Goentoro LA, Reeves GT, Kowal CP, Martinelli L, Schupbach T, Shvartsman SY. (2006) Quantifying the Gurken morphogen gradient in Drosophila oogenesis. Dev Cell. 11: 263-72. PubMed
Yakoby N, Bristow CA, Gouzman I,...Shvartsman SY. (2006) Systems-level questions in Drosophila oogenesis. Syst Biol. 152: 276-84. PubMed
Reeves GT, Muratov CB, Schupbach T, Shvartsman SY. (2006) Quantitative models of developmental pattern formation. Dev Cell. 11: 289-300. PubMed
Nikolic DL, Boettiger AN, Bar-Sagi D, Carbeck JD, Shvartsman SY. (2006) The role of boundary conditions in the experimental model of wound healing. Am J Physiol Cell Physiol. 1: C68-75. PubMed
Berezhkovskii AM, Monine MI, Muratov CB, Shvartsman SY. (2006) Homogenization of boundary conditions for surfaces with regular arrays of traps. J Chem Phys. 124: 036103. PubMed
Goentoro LA, Yakoby N, Goodhouse J, Schupbach T, Shvartsman SY. (2006) Quantitative analysis of the GAL4/UAS system in Drosophila oogenesis. Genesis. 44: 66-74. PubMed
Reeves GT, Kalifa R, Klein DE, Lemmon MA, Shvartsman SY. (2005). Computational analysis of EGFR inhibition by Argos. Dev Biol. 284: 523-35. PubMed
Shvartsman SY (2005). Quantitative analysis of developing tissues. AIChE Journal 51: 1312 - 1318.
Monine MI, Berezhkovskii AM, Joslin EJ, Wiley HS, Lauffenburger DA, Shvartsman SY. (2005) Ligand accumulation in autocrine cell cultures. Biophys J. 88: 2384-90. PubMed
Berezhkovskii AM, Makhnovskii YA, Monine MI, Zitserman VY, Shvartsman SY. (2004) Boundary homogenization for trapping by patchy surfaces. J Chem Phys. 121: 11390-94. PubMed
Muratov CB, Shvartsman SY. (2004) Signal propagation and failure in discrete autocrine relays. Phys Rev Lett. 93: 118101. PubMed
Shvartsman SY, Wiley HS, Lauffenburger DA. (2004) Epidermal growth factor receptor signaling in tissues. IEEE Cont Sys Mag. 24: 53-61.
Klein DE, Nappi VM, Reeves GT, Shvartsman SY, Lemmon MA. (2004) Argos inhibits epidermal growth factor receptor signalling by ligand sequestration. Nature. 430: 1040-44. PubMed
Berezhkovskii AM, Batsilas L, Shvartsman SY. (2004) Ligand trapping in epithelial layers and cell cultures. Biophys Chem. 107: 221-27. PubMed
Berezhkovskii AM, Zitserman Yu, Shvartsman SY. (2003) Diffusivity in periodic arrays of spherical cavities. J Chem Phys. 118: 7146-47.
Berezhkovskii AM, Zitserman Yu, Shvartsman SY. (2003) Effective diffusivity in periodic porous materials. J Chem Phys. 119: 6991-93.
Muratov CB, Shvartsman SY. (2003) An asymptotic study of the inductive pattern formation mechanism in Drosophila egg development. Physica D, Nonlinear Phenomena. 186: 93-108.
Batsilas L, Berezhkovskii AM, Shvartsman SY. (2003) Stochastic model of autocrine and paracrine signals in cell culture assays. Biophys J. 85: 3659-65. PubMed
Wiley HS, Shvartsman SY, Lauffenburger DA. (2003) Computational modeling of the EGF-receptor system: a paradigm for systems biology. Trends Cell Biol. 13: 43-50. PubMed
Pribyl M, Muratov CB, Shvartsman SY. (2003) Discrete models of autocrine cell communication in epithelial layers. Biophys J. 84: 3624-35. PubMed
Pribyl M, Muratov CB, Shvartsman SY. (2003) Long-range signal transmission in autocrine relays. Biophys J. 84: 883-96. PubMed
Pribyl M, Muratov CB, Shvartsman SY. (2003) Transitions in the model of epithelial patterning. Dev Dyn. 226: 155-59. PubMed
Shvartsman SY, Muratov CB, Lauffenburger DA. (2002) Modeling and computational analysis of EGF receptor-mediated cell communication in Drosophila oogenesis. Development. 129:PubMed.
Shvartsman SY, Hagan MP, Yacoub A, Dent P, Wiley HS, Lauffenburger DA. (2002) Autocrine loops with positive feedback enable context-dependent cell signaling. Am J Physiol Cell Physiol. 282: C545-59. PubMed