Biologists Describe Key Mechanism in Early Embryo Development
ScienceDaily (Oct. 20, 2011) — New York University and University of Iowa biologists have identified a key mechanism controlling early embryonic development that is critical in determining how structures such as appendages -- arms and legs in humans -- grow in the right place and at the right time.
NYU and University of Iowa biologists have identified a key mechanism controlling early embryonic development that is critical in determining how structures such as appendages—arms and legs in humans—grow in the right place and at the right time. The researchers used Drosophila, or fruit flies, to investigate these regulatory networks. Pictured above is a fruit fly embryo. (Credit: Image courtesy of PLoS Genetics.)
In a paper published in the journal PLoS Genetics, John Manak, an assistant professor of biology in the UI College of Liberal Arts and Sciences, and Chris Rushlow, a professor in NYU's Department of Biology, write that much research has focused on the spatial regulatory networks that control early developmental processes. However, they note, less attention has been paid to how such networks can be precisely coordinated over time.
Rushlow and Manak find that a protein called Zelda is responsible for turning on groups of genes essential to development in an exquisitely coordinated fashion.
"Zelda does more than initiate gene networks -- it orchestrates their activities so that the embryo undergoes developmental processes in a robust manner at the proper time and in the correct order," says Rushlow, part of NYU's Center for Developmental Genetics.
"Our results demonstrate the significance of a timing mechanism in coordinating regulatory gene networks during early development, and bring a new perspective to classical concepts of how spatial regulation can be achieved," says Manak, who is also assistant professor of pediatrics in the Roy J. and Lucille A. Carver College of Medicine and researcher in the UI Roy J. Carver Center for Genomics.
The researchers note that their findings break new ground.
"We discovered a key transcriptional regulator, Zelda, which is the long-sought-after factor that activates the early zygotic genome," says Rushlow.
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Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo
Chung-Yi Nien1#, Hsiao-Lan Liang1#, Stephen Butcher2, Yujia Sun1, Shengbo Fu1, Tenzin Gocha1, Nikolai Kirov1, J. Robert Manak2*,Christine Rushlow1*
1 Department of Biology, Center for Developmental Genetics, New York University, New York, New York, United States of America, 2 Departments of Biology and Pediatrics, Roy J. Carver Center for Genomics, University of Iowa, Iowa City, Iowa, United States of America
Abstract
In past years, much attention has focused on the gene networks that regulate early developmental processes, but less attention has been paid to how multiple networks and processes are temporally coordinated. Recently the discovery of the transcriptional activator Zelda (Zld), which binds to CAGGTAG and related sequences present in the enhancers of many early-activated genes in Drosophila, hinted at a mechanism for how batteries of genes could be simultaneously activated. Here we use genome-wide binding and expression assays to identify Zld target genes in the early embryo with the goal of unraveling the gene circuitry regulated by Zld. We found that Zld binds to genes involved in early developmental processes such as cellularization, sex determination, neurogenesis, and pattern formation. In the absence of Zld, many target genes failed to be activated, while others, particularly the patterning genes, exhibited delayed transcriptional activation, some of which also showed weak and/or sporadic expression. These effects disrupted the normal sequence of patterning-gene interactions and resulted in highly altered spatial expression patterns, demonstrating the significance of a timing mechanism in early development. In addition, we observed prevalent overlap between Zld-bound regions and genomic “hotspot” regions, which are bound by many developmental transcription factors, especially the patterning factors. This, along with the finding that the most over-represented motif in hotspots, CAGGTA, is the Zld binding site, implicates Zld in promoting hotspot formation. We propose that Zld promotes timely and robust transcriptional activation of early-gene networks so that developmental events are coordinated and cell fates are established properly in the cellular blastoderm embryo.
Author Summary
Development of a fertilized egg into a multicellular organism comprises a series of precisely timed events initially controlled by factors deposited into the egg. Some of these factors are localized to specific regions of the embryo and instruct cells to adopt certain fates. In this way, these “morphogen” factors lend pattern to the body plan so that different appendages are formed in the right places. In contrast, other factors are evenly distributed throughout the embryo and regulate processes concerning all cells. For example, in Drosophila, Zld is a ubiquitous factor that collectively activates batteries of genes essential for further development. Here we show that Zld also functions alongside the spatial morphogens to ensure timely and robust activation of their target genes. In the absence of Zld, activation of these genes is delayed, which derails the proper order of gene interactions and ultimately disrupts gene expression patterns. Our results demonstrate the significance of a timing mechanism in coordinating regulatory gene networks during early development, and they bring a new perspective to classical concepts of how spatial regulation can be achieved.
Citation: Nien C-Y, Liang H-L, Butcher S, Sun Y, Fu S, et al. (2011) Temporal Coordination of Gene Networks by Zelda in the Early Drosophila Embryo. PLoS Genet 7(10): e1002339. doi:10.1371/journal.pgen.1002339
Editor: Gregory S. Barsh, Stanford University School of Medicine, United States of America
Received: August 19, 2011; Accepted: August 29, 2011; Published: October 20, 2011
Copyright: © 2011 Nien et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by a grant from the National Institutes of Health (GM63024). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: chris.rushlow@nyu.edu (CR); john-manak@uiowa.edu (JRM)
# These authors contributed equally to this work.
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