The proposed work falls into three general areas. The Initial objective is to extend solved gene regulatory networks (GRNs) controlling sea urchin embryonic specification, up to gastrula stage, to encompass the whole of the embryo. This will require de novo solution for one remaining complex domain of the embryo. Following this we will build a predictive digital computational model of regulatory specification throughout the embryo from a few h after fertilization to 30h, including all interactions between domains, using the approach and software recently applied to the endomesodermal half of the embryo. A second objective is to utilize synthetic re-engineering to ascertain the logic processing functions and to answer other questions about the meaning of particular network subcircuit designs encountered in the sea urchin endomesoderm GRN. Specifically we will target double negative gate circuitry, feedback circuitry, and also redeploy differentiation gene batteries. These studies will be carried out in the context of the developing embryo, rather than in isolated """"""""toy"""""""" circuits, and will utilize combinations of recombineered BACs. Thirdly a set of collaborative proposals is presented in which the Davidson lab will work together with the McClay lab on their major objective of deciphering the control circuitry for morphogenetic functions, and the Davidson lab will work together with the Bronner lab to aid in their objective of obtaining comparative GRN analysis between cranial and trunk neural crest.

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 fon/vard 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 #
2P01HD037105-16
Application #
8752112
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (ED))
Project Start
2014-06-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
16
Fiscal Year
2014
Total Cost
$633,926
Indirect Cost
$243,549
Name
California Institute of Technology
Department
Type
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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 411:314-24
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
Simoes-Costa, Marcos; Bronner, Marianne E (2016) Reprogramming of avian neural crest axial identity and cell fate. Science 352:1570-3
Bronner, Marianne E (2016) How inhibitory cues can both constrain and promote cell migration. J Cell Biol 213:505-7
Uribe, Rosa A; Gu, Tiffany; Bronner, Marianne E (2016) A novel subset of enteric neurons revealed by ptf1a:GFP in the developing zebrafish enteric nervous system. Genesis 54:123-8
Hochgreb-Hagele, Tatiana; Koo, Daniel E S; Bronner, Marianne E (2015) Znf385C mediates a novel p53-dependent transcriptional switch to control timing of facial bone formation. Dev Biol 400:23-32
Butler, Samantha J; Bronner, Marianne E (2015) From classical to current: analyzing peripheral nervous system and spinal cord lineage and fate. Dev Biol 398:135-46
Simões-Costa, Marcos; Stone, Michael; Bronner, Marianne E (2015) Axud1 Integrates Wnt Signaling and Transcriptional Inputs to Drive Neural Crest Formation. Dev Cell 34:544-54
Barriga, Elias H; Trainor, Paul A; Bronner, Marianne et al. (2015) Animal models for studying neural crest development: is the mouse different? Development 142:1555-60
Martik, Megan L; McClay, David R (2015) Deployment of a retinal determination gene network drives directed cell migration in the sea urchin embryo. Elife 4:

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