This is an application for continuation and broadening of a Program Project now in its 9th year. Here we propose to build in many directions on the large success we have had in solving and authenticating a gene regulatory network (GRN) for development. GRNs provide causal explanations for developmental processes in the terms of the genomic regulatory code, where all species-specific developmental processes are ultimately programmed. A developmental GRN serves as a conceptual, system-level logic map, of direct predictive power. Thus GRNs bridge between functional genomic DNA sequence of regulatory significance and the biology of embryogenesis and body plan formation. They do this by specifying the regulatory interactions which causally drive the progression of regulatory states in diverse cellular territories. During recent years, this Program has been responsible for the experimental solution of the most advanced developmental GRN yet available for any developing animal organism. This is the GRN underlying the specification of the endomesodermal territories of the sea urchin embryo. Recently proof of the principle that as a GRN approaches completion it indeed provides explanation of all the observed biological functions has been obtained in this work. We now intend to capitalize on the growing suite of successful technological approaches to GRN analysis that we have developed, to confront challenges that heretofore were inaccessible, or could not even have been defined. The current sea urchin embryo GRN concerns about half of the embryo, that ultimately forming the gut, the skeletogenic cell lineages and the non-skeletogenic mesoderm, from the earliest zygotic genomic activity (at the beginning of cleavage) to just before gastrulation. A start on the oral and aboral ectodermal GRNs has also been made. We intend to expand this GRN in qualitatively distinct ways which will represent radical advances if successful. In the DAVIDSON COMPONENT the GRN will be expanded to include all regulatory genes predicted by genomic analysis, and observed to be expressed specifically in the endomesodermal territories, (cont.)

Public Health Relevance

The only way medical practice will advance beyond elegant forms of bandaids and single molecule drug targets will be by interventions at the level of organization that life systems actually operate, particularly the control systems. This Project concerns the most advanced example of genomic control systems biology we have at present. Its successful conclusion will show what the structure of these systems is;how to think about intervening in them;and directly inform considerations of the role of developmentally active regulatory gene mutations in the many forms of human developmental genetic disease we have become aware of. The medical research community is well aware of these points and the Pis of this application are frequently asked by forward looking members of it for collaborations, consultations, symposium presentations etc.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD037105-15
Application #
8471131
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (DE))
Program Officer
Coulombe, James N
Project Start
1999-04-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
15
Fiscal Year
2013
Total Cost
$1,542,376
Indirect Cost
$494,904
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Martik, Megan L; McClay, David R (2017) New insights from a high-resolution look at gastrulation in the sea urchin, Lytechinus variegatus. Mech Dev 148:3-10
Roellig, Daniela; Tan-Cabugao, Johanna; Esaian, Sevan et al. (2017) Dynamic transcriptional signature and cell fate analysis reveals plasticity of individual neural plate border cells. Elife 6:
Lignell, Antti; Kerosuo, Laura; Streichan, Sebastian J et al. (2017) Identification of a neural crest stem cell niche by Spatial Genomic Analysis. Nat Commun 8:1830
Murko, Christina; Bronner, Marianne E (2017) Tissue specific regulation of the chick Sox10E1 enhancer by different Sox family members. Dev Biol 422:47-57
Gandhi, Shashank; Piacentino, Michael L; Vieceli, Felipe M et al. (2017) Optimization of CRISPR/Cas9 genome editing for loss-of-function in the early chick embryo. Dev Biol 432:86-97
Martik, Megan L; Bronner, Marianne E (2017) Regulatory Logic Underlying Diversification of the Neural Crest. Trends Genet 33:715-727
Martik, Megan L; Lyons, Deirdre C; McClay, David R (2016) Developmental gene regulatory networks in sea urchins and what we can learn from them. F1000Res 5:
Roellig, Daniela; Bronner, Marianne E (2016) The epigenetic modifier DNMT3A is necessary for proper otic placode formation. Dev Biol 411:294-300
Warner, Jacob F; Miranda, Esther L; McClay, David R (2016) Contribution of hedgehog signaling to the establishment of left-right asymmetry in the sea urchin. Dev Biol 411:314-324
Peter, Isabelle S; Davidson, Eric H (2016) Implications of Developmental Gene Regulatory Networks Inside and Outside Developmental Biology. Curr Top Dev Biol 117:237-51

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