At the molecular, cellular and multicellular level, the spatial and temporal generation of biological organization is the product of the interaction of many independent components within biological networks. These networks constitute complex systems with properties greater than the sum of the constituent parts. During somitogenesis, a temporal patterning mechanism, the oscillator, gives rise to a emergent spatial pattern that presages the formation of morphological segments. This oscillator creates stripes/waves of gene expression that repeatedly travel through the field of cells about to undergo segmentation. Our first objective is to establish a more detailed chronology of the cyclical changes in gene expression and morphology that occur during zebrafish somitogenesis using vivo imaging, carefully staged embryos and fluorescent in situ hybridization. Recent work, including our own, has found that the Notch signaling pathway has successive functions in both the oscillator mechanism and in a later process that more directly regulates morphological segmentation. In the zebrafish, we have shown that the Notch ligands aei/deltaD, bea/deltaC and Notch target gene her1 each function within the oscillator mechanism, but each has a distinct mutant phenotype.
Our second aim i s to distinguish the functions of the two delta homologs by comparative phenotypic analysis of the two delta mutants, double mutant analysis, ectopic expression experiments and genetic mosaics. We hypothesize that aei/deltaD and beaJdeltaC have distinct signaling roles within the oscillator circuit and that the relative function and intensities of the delta signals vary at different positions within the segmenting tissue.
The third aim examines the function of her1 within the oscillator. We will determine if Her1 protein levels oscillate and if the stability of the protein determines the frequency of the oscillator.
The final aim i s to develop a real-time readout of the oscillator in order to visualize the oscillations in live embryos. Cumulatively, these experiments address how local signaling interactions between a cell and its immediate neighbors via the Notch pathway give rise to an emergent, higher-level of organization within the paraxial mesoderm. This analysis of the genetic network that governs somitogenesis is central to our understanding of vertebrate development and has broad implications concerning the complex properties of biological circuits.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD045738-05
Application #
7417576
Study Section
Special Emphasis Panel (ZRG1-DEV-1 (01))
Program Officer
Javois, Lorette Claire
Project Start
2004-07-01
Project End
2009-08-31
Budget Start
2008-05-01
Budget End
2009-08-31
Support Year
5
Fiscal Year
2008
Total Cost
$307,337
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Schwendinger-Schreck, Jamie; Kang, Yuan; Holley, Scott A (2014) Modeling the zebrafish segmentation clock's gene regulatory network constrained by expression data suggests evolutionary transitions between oscillating and nonoscillating transcription. Genetics 197:725-38
Dray, Nicolas; Lawton, Andrew; Nandi, Amitabha et al. (2013) Cell-fibronectin interactions propel vertebrate trunk elongation via tissue mechanics. Curr Biol 23:1335-41
Lawton, Andrew K; Nandi, Amitabha; Stulberg, Michael J et al. (2013) Regulated tissue fluidity steers zebrafish body elongation. Development 140:573-82
Stulberg, Michael J; Lin, Aiping; Zhao, Hongyu et al. (2012) Crosstalk between Fgf and Wnt signaling in the zebrafish tailbud. Dev Biol 369:298-307
Trofka, Anna; Schwendinger-Schreck, Jamie; Brend, Tim et al. (2012) The Her7 node modulates the network topology of the zebrafish segmentation clock via sequestration of the Hes6 hub. Development 139:940-7
Brend, Tim; Holley, Scott A (2009) Expression of the oscillating gene her1 is directly regulated by Hairy/Enhancer of Split, T-box, and Suppressor of Hairless proteins in the zebrafish segmentation clock. Dev Dyn 238:2745-59
Zhang, Lixia; Kendrick, Christina; Julich, Dorthe et al. (2008) Cell cycle progression is required for zebrafish somite morphogenesis but not segmentation clock function. Development 135:2065-70
Mara, Andrew; Schroeder, Joshua; Holley, Scott A (2008) Two deltaC splice-variants have distinct signaling abilities during somitogenesis and midline patterning. Dev Biol 318:126-32
Mara, Andrew; Schroeder, Joshua; Chalouni, Cecile et al. (2007) Priming, initiation and synchronization of the segmentation clock by deltaD and deltaC. Nat Cell Biol 9:523-30
Holley, Scott A (2007) The genetics and embryology of zebrafish metamerism. Dev Dyn 236:1422-49

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