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Global regulatory logic for specification of an embryonic cell lineage

Oliveri, Paola and Tu, Qiang and Davidson, Eric H. (2008) Global regulatory logic for specification of an embryonic cell lineage. Proceedings of the National Academy of Sciences of the United States of America, 105 (16). pp. 5955-5962. ISSN 0027-8424. PMCID PMC2329687. doi:10.1073/pnas.0711220105.

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Explanation of a process of development must ultimately be couched in the terms of the genomic regulatory code. Specification of an embryonic cell lineage is driven by a network of interactions among genes encoding transcription factors. Here, we present the gene regulatory network (GRN) that directs the specification of the skeletogenic micromere lineage of the sea urchin embryo. The GRN now includes all regulatory genes expressed in this lineage up to late blastula stage, as identified in a genomewide survey. The architecture of the GRN was established by a large-scale perturbation analysis in which the expression of each gene in the GRN was cut off by use of morpholinos, and the effects on all other genes were measured quantitatively. Several cis-regulatory analyses provided additional evidence. The explanatory power of the GRN suffices to provide a causal explanation for all observable developmental functions of the micromere lineage during the specification period. These functions are: (i) initial acquisition of identity through transcriptional interpretation of localized maternal cues; (ii) activation of specific regulatory genes by use of a double negative gate; (iii) dynamic stabilization of the regulatory state by activation of a feedback subcircuit; (iv) exclusion of alternative regulatory states; (v) presentation of a signal required by the micromeres themselves and of two different signals required for development of adjacent endomesodermal lineages; and (vi) lineage-specific activation of batteries of skeletogenic genes. The GRN precisely predicts gene expression responses and provides a coherent explanation of the biology of specification.

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Additional Information:© 2008 by The National Academy of Sciences of the USA. This Feature Article is part of a series identified by the Editorial Board as reporting findings of exceptional significance. Edited by Gertrud M. Schüpbach, Princeton University, Princeton, NJ, and approved January 31, 2008 (received for review December 14, 2007). This article is a PNAS Direct Submission. Published online before print April 14, 2008, doi: 10.1073/pnas.0711220105. We thank Jina Jun for superb and essential technical assistance and Prof. Ellen Rothenberg and Dr. Andy Ransick for valuable comments. This research was supported by National Institutes of Health Grants HD-37105 and GM-61005, the Lucile P. Markey Charitable Trust, and the Camilla Chandler Frost Fellowship (to P.O.). Author contributions: P.O. and Q.T. contributed equally to this work; P.O. and E.H.D. designed research; P.O. and Q.T. performed research; P.O., Q.T., and E.H.D. analyzed data; and P.O. and E.H.D. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Lucile P. Markey Charitable TrustUNSPECIFIED
Camilla Chandler Frost FellowshipUNSPECIFIED
Subject Keywords:gene regulatory networks; network subcircuits; sea urchin embryo; skeletogenic micromeres
Issue or Number:16
PubMed Central ID:PMC2329687
Record Number:CaltechAUTHORS:OLIpnas08
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11255
Deposited By: Archive Administrator
Deposited On:28 Jul 2008 21:37
Last Modified:08 Nov 2021 21:56

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