Dynamics and heterogeneity of a fate determinant during transition towards cell differentiation

Yan is an ETS-domain transcription factor responsible for maintaining Drosophila eye cells in a multipotent state. Yan is at the core of a regulatory network that determines the time and place in which cells transit from multipotency to one of several differentiated lineages. Using a fluorescent reporter for Yan expression, we observed a biphasic distribution of Yan in multipotent cells, with a rapid inductive phase and slow decay phase. Transitions to various differentiated states occurred over the course of this dynamic process, suggesting that Yan expression level does not strongly determine cell potential. Consistent with this conclusion, perturbing Yan expression by varying gene dosage had no effect on cell fate transitions. However, we observed that as cells transited to differentiation, Yan expression became highly heterogeneous and this heterogeneity was transient. Signals received via the EGF Receptor were necessary for the transience in Yan noise since genetic loss caused sustained noise. Since these signals are essential for eye cells to differentiate, we suggest that dynamic heterogeneity of Yan is a necessary element of the transition process, and cell states are stabilized through noise reduction. DOI: http://dx.doi.org/10.7554/eLife.08924.001

[1]  Aviv Regev,et al.  Deconstructing transcriptional heterogeneity in pluripotent stem cells , 2014, Nature.

[2]  B. Shilo.  The regulation and functions of MAPK pathways in Drosophila. , 2014, Methods.

[3]  M. Torres-Padilla,et al.  Transcription factor heterogeneity in pluripotent stem cells: a stochastic advantage , 2014, Development.

[4]  Justin J. Cassidy,et al.  A comparative study of Pointed and Yan expression reveals new complexity to the transcriptional networks downstream of receptor tyrosine kinase signaling. , 2014, Developmental biology.

[5]  Aggelos K. Katsaggelos,et al.  Drosophila eye nuclei segmentation based on graph cut and convex shape prior , 2013, 2013 IEEE International Conference on Image Processing.

[6]  Hao Yuan Kueh,et al.  Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation , 2013, Science.

[7]  Ben D. MacArthur,et al.  Statistical Mechanics of Pluripotency , 2013, Cell.

[8]  P. Cahan,et al.  Origins and implications of pluripotent stem cell variability and heterogeneity , 2013, Nature Reviews Molecular Cell Biology.

[9]  K. White,et al.  The Relationship Between Long-Range Chromatin Occupancy and Polymerization of the Drosophila ETS Family Transcriptional Repressor Yan , 2013, Genetics.

[10]  Robert Ahrends,et al.  Consecutive Positive Feedback Loops Create a Bistable Switch that Controls Preadipocyte-to-Adipocyte Conversion , 2012, Cell reports.

[11]  Joshua M Brickman,et al.  Gene expression heterogeneities in embryonic stem cell populations: origin and function. , 2011, Current opinion in cell biology.

[12]  A. Kicheva,et al.  Dynamics of Dpp Signaling and Proliferation Control , 2011, Science.

[13]  Aaron R Dinner,et al.  Modeling bistable cell-fate choices in the Drosophila eye: qualitative and quantitative perspectives , 2010, Development.

[14]  M. Sander,et al.  Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors. , 2010, Developmental cell.

[15]  Lea Goentoro,et al.  Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling. , 2009, Molecular cell.

[16]  Uri Alon,et al.  Dynamics and variability of ERK2 response to EGF in individual living cells. , 2009, Molecular cell.

[17]  U. Alon,et al.  The incoherent feedforward loop can provide fold-change detection in gene regulation. , 2009, Molecular cell.

[18]  Justin J. Cassidy,et al.  A MicroRNA Imparts Robustness against Environmental Fluctuation during Development , 2009, Cell.

[19]  R. Carthew,et al.  Cell-type-specific transcription of prospero is controlled by combinatorial signaling in the Drosophila eye , 2008, Development.

[20]  Hannah H. Chang,et al.  Transcriptome-wide noise controls lineage choice in mammalian progenitor cells , 2008, Nature.

[21]  Tae J. Lee,et al.  A bistable Rb–E2F switch underlies the restriction point , 2008, Nature Cell Biology.

[22]  Manu,et al.  Characterization of the Drosophila segment determination morphome. , 2008, Developmental biology.

[23]  S. Tapscott,et al.  Reciprocal inhibition between Pax7 and muscle regulatory factors modulates myogenic cell fate determination , 2007, The Journal of cell biology.

[24]  P. Lásló,et al.  Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates , 2006, Cell.

[25]  Naama Barkai,et al.  Threshold responses to morphogen gradients by zero-order ultrasensitivity , 2005, Molecular systems biology.

[26]  Thomas Labhart,et al.  Homothorax Switches Function of Drosophila Photoreceptors from Color to Polarized Light Sensors , 2003, Cell.

[27]  K. Saigo,et al.  Ligand-dependent activation of breathless FGF receptor gene in Drosophila developing trachea , 2002, Mechanisms of Development.

[28]  Jeffrey M. Hausdorff,et al.  Fractal dynamics in physiology: Alterations with disease and aging , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[29]  R. Carthew,et al.  Overlapping Activators and Repressors Delimit Transcriptional Response to Receptor Tyrosine Kinase Signals in the Drosophila Eye , 2000, Cell.

[30]  Stephen S. Gisselbrecht,et al.  Ras Pathway Specificity Is Determined by the Integration of Multiple Signal-Activated and Tissue-Restricted Transcription Factors , 2000, Cell.

[31]  U. Banerjee,et al.  Combinatorial Signaling in the Specification of Unique Cell Fates , 2000, Cell.

[32]  T. Jessell,et al.  A Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural Tube , 2000, Cell.

[33]  J P Kumar,et al.  Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation. , 1998, Development.

[34]  V. Hartenstein,et al.  EGFR signaling is required for the differentiation and maintenance of neural progenitors along the dorsal midline of the Drosophila embryonic head. , 1998, Development.

[35]  E. Hafen,et al.  Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye. , 1997, Genes & development.

[36]  J. S. Britton,et al.  Pointed, an ETS domain transcription factor, negatively regulates the EGF receptor pathway in Drosophila oogenesis. , 1996, Development.

[37]  M. Freeman,et al.  Reiterative Use of the EGF Receptor Triggers Differentiation of All Cell Types in the Drosophila Eye , 1996, Cell.

[38]  B. Shilo,et al.  The Drosophila embryonic midline is the site of Spitz processing, and induces activation of the EGF receptor in the ventral ectoderm. , 1996, Development.

[39]  B. Shilo,et al.  EGF receptor signaling induces pointed P1 transcription and inactivates Yan protein in the Drosophila embryonic ventral ectoderm. , 1996, Development.

[40]  J. Zhang,et al.  Ras1 signaling and transcriptional competence in the R7 cell of Drosophila. , 1996, Genes & development.

[41]  V. Hartenstein,et al.  The role of yan in mediating the choice between cell division and differentiation. , 1995, Development.

[42]  Gerald M Rubin,et al.  Yan functions as a general inhibitor of differentiation and is negatively regulated by activation of the Ras1/MAPK pathway , 1995, Cell.

[43]  Gerald M. Rubin,et al.  The activities of two Ets-related transcription factors required for drosophila eye development are modulated by the Ras/MAPK pathway , 1994, Cell.

[44]  Yuh Nung Jan,et al.  atonal is the proneural gene for Drosophila photoreceptors , 1994, Nature.

[45]  E. Hafen,et al.  A gain-of-function mutation in Drosophila MAP kinase activates multiple receptor tyrosine kinase signaling pathways , 1994, Cell.

[46]  Gerald M. Rubin,et al.  Negative control of photoreceptor development in Drosophila by the product of the yan gene, an ETS domain protein , 1992, Cell.

[47]  G. Rubin,et al.  Signalling by the sevenless protein tyrosine kinase is mimicked by Rasl activation , 1992, Nature.

[48]  T. Schüpbach,et al.  Coordinately and differentially mutable activities of torpedo, the Drosophila melanogaster homolog of the vertebrate EGF receptor gene. , 1989, Genetics.

[49]  E. Hafen,et al.  Dynamics of Drosophila eye development and temporal requirements of sevenless expression. , 1989, Development.

[50]  S. Zipursky,et al.  Analysis of mutants in chaoptin, a photoreceptor cell-specific glycoprotein in Drosophila, reveals its role in cellular morphogenesis , 1988, Cell.

[51]  D. Ready,et al.  Neuronal differentiation in Drosophila ommatidium. , 1987, Developmental biology.

[52]  D. Ready,et al.  Ommatidial development in Drosophila eye disc fragments. , 1986, Developmental biology.

[53]  A. Tomlinson.  The cellular dynamics of pattern formation in the eye of Drosophila. , 1985, Journal of embryology and experimental morphology.

[54]  C. Nüsslein-Volhard,et al.  Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster , 1984, Wilhelm Roux's archives of developmental biology.

[55]  J. Campos-Ortega,et al.  Cell clones and pattern formation: On the lineage of photoreceptor cells in the compound eye ofDrosophila , 1977, Wilhelm Roux's archives of developmental biology.

[56]  S. Benzer,et al.  Development of the Drosophila retina, a neurocrystalline lattice. , 1976, Developmental biology.

[57]  J. Lucchesi,et al.  Regulation of gene function: A comparison of enzyme activity levels in relation to gene dosage in diploids and triploids of Drosophila melanogaster , 1973, Biochemical Genetics.

[58]  M. Bate,et al.  The development of Drosophila melanogaster , 2009 .

[59]  J. Treisman,et al.  Wingless signaling in Drosophila eye development. , 2008, Methods in molecular biology.

[60]  C. Nüsslein-Volhard,et al.  Mutations affecting the pattern of the larval cuticle inDrosophila melanogaster , 2004, Wilhelm Roux's archives of developmental biology.