Head of the Lab: Dr. Smadar Ben Tabou deLeon
We aim to decipher how the genomic program for development is encoded in the DNA, how it is executed during development and what enables it to resist genetic and environmental changes. We study sea urchin and other echinoderm species that have major experimental advantages that enable us to investigate the regulation of developmental process starting from fertilization. Our research has strong implications to the understanding of cell fate specification and differentiation as well as dedifferentiation processes that occur during genetic diseases, like cancer.
Fresh from our lab
We are recruiting M.Sc. and Ph.D. students. If you are interested please send your CV and research interests to: email@example.com
GENERAL: From Cnidaria to humans, animals share similar sets of genes yet have radically different body plans; the difference lies in the organization of these genes in developmental gene regulatory networks (GRNs). We are addressing fundamental challenges in developmental, evolutionary and ecological studiesby studying the regulatory networks that drive the sea urchin embryo development. Current projects in the lab are:
Vascular Endothelial Growth Factor (VEGF) pathway and sea urchin larval skeletogenesis as a model for human angiogenesis: During angiogenesis, a tumor secrets VEGF ligand to induces the growth of new blood vessels toward the tumor, enabling the tumor to grow and metastasize. In the sea urchin embryo that doesn’t have a blood vessel; VEGF is essential factor in skeletogenesis. In new experiments from our lab we showed that human VEGF is capable of generating ectopic skeleton in the sea urchin and that VEGF targets in the sea urchin are similar to those it activates during angiogenesis. We are now studying the molecular pathways activated by VEGF during sea urchin skeletogenesis to provide better understanding of this pathway and open the way to new therapeutic approaches. This research involves advanced quantitative methods of molecular biology and imaging.
Comparative studies of transcriptional programs between echinoderm species: The differences between the developmental transcriptional programs of different organisms underlie their different morphologies. We are studying the relation between the expression patterns of different echinoderm species and their different morphologies, to understand the evolutionary changes that underlie the emergence of new species.
Deciphering the molecular mechanisms that help developmental gene regulatory networks evade major threats, such as polution and global warming is critical to the maintainence of biodiversity. Here we use the sea urchin embryo as a model system to study the response of basic developmental regulatory mechanisms to environmental changes. We discovered that embryo development is substantially delayed in the coastal sea water that are polluted and highly salinated. We now study the specific molecular mechanisms affected by these conditions in order to understand the risks to coastal biosystems.
Previous related publications
Smadar Ben-Tabou de-Leon, Yi-Hsien Su, Kuan-Ting Lin, Enhu Li and Eric H. Davidson, Gene Regulatory Control in the Sea Urchin Aboral Ectoderm: Spatial Initiation, Signaling Inputs, and Cell Fate Lockdown, Dev. Biol., 374, 245-254 (2013) .PDF In this paper we study the regulation of the secondary axis formation (oral-aboral) in sea urchin. Our analysis illuminates a dynamic system where different factors dominate at different developmental times. We discovered that the initial activation of aboral genes depends directly on the redox sensitive transcription factor, hypoxia inducible factor 1α (HIF-1α). Two BMP ligands, BMP2/4 and BMP5/8, then significantly enhance aboral regulatory gene transcription. Ultimately, encoded feedback wiring lockdown the aboral ectoderm regulatory state. Our study elucidates the different regulatory mechanisms that sequentially dominate the spatial localization of aboral regulatory states.
Smadar Ben-Tabou de-Leon, The conserved role and divergent regulation of foxa, a pan-eumetazoan developmental regulatory gene, Dev. Biol. 357, 21-26 (2011). PDF.
In this paper the transcriptional regulation and the developmental role of the transcription factor foxa are reviewed. While foxa developmental role in mesenchymal to epithelial transition is higly conserved among bilaterias, the upstream regulation of foxa had diverged signifcantly.This might imply that the similarity of foxa knock-down phenotype is due to its role in an ancestral gene regulatory network that controlled intercalation followed by mesenchymal-to-epithelial transition. foxa transcriptional regulation had evolved to support the developmental program in each species so foxa would play its role controlling morphogenesis at the necessary embryonic address.
Smadar Ben-Tabou de-Leon, Perturbation Analysis Analyzed - Mathematical Modeling of Intact and Perturbed Gene Regulatory Subcircuits for Animal Development, Dev. Biol. 344, 1110-1118 (2010). PDF.
In this paper mathematical modeling is used to study the dynamics of gene regulatory circuits to advance the ability to infer regulatory connections and logic function from experimental data. We study the effect of a perturbation of an input on the level of its downstream genes and compare between the cis-regulatory execution of OR and AND logics. The model improves our ability to analyze experimental data and construct from it the network topology. The model also illuminates the information processing properties of gene regulatory circuits for animal development.
Smadar Ben-Tabou de-Leon and Eric H. Davidson, Information Processing at the foxa Node of the Sea Urchin Endomesoderm Specification Network, PNAS, 107, 10103-10108 (2010). PDF.
In this paper we dissect the cis-regulation of the transcription factor foxa, a key regulatory gene in the endoderm specification accross bilateria. We found that no fewer than four cis-regulatory modules interact with each other and switch their dominance in controlling foxa expression in different spatial domains and at different times. we found that foxa expression is cleared from the mesoderm and is restricted to the endoderm due to Tcf-Groucho derepression caused by βcatenin clearance from the nucleus of the mesodermal cells. Our discovery led to the understanding that the mesodermal clearance of endodermal genes controlled by Wnt/βcatenin is essential for the specification of the mesoderm and is a key mechanism controlling the endoderm–mesoderm cell fate decision. Tcf-Groucho/βcatenin clearance mechanism is relevant to many systems, including vertebrates and nematodes, as the role of the Wnt-βcatenin pathway in promoting endodermal fate and repressing mesodermal fate is highly conserved.
Smadar Ben-Tabou de-Leonand Eric H. Davidson, Experimentally Based Sea Urchin Gene Regulatory Network and the Causal Explanation of Developmental Phenomenology, Wiley interdisciplinary reviews, systems biology, 1(2), 237-246 (2009). NCBI.
This is a review of the prominant features of the gene regulatory network that governs the endomesoderm specification in the sea urchin embyro. The network explains the mechanisms utilized in development to control the formation of dynamic expression patterns of transcription factors and signaling molecules. Comparing the sea urchin gene regulatory network to that of the sea star and to that of later developmental stages in the sea urchin, reveals mechanisms underlying the origin of evolutionary novelty.
Smadar Ben-Tabou de-Leonand Eric Davidson, Modeling the dynamics of transcriptional gene regulatory networks for animal development, Dev. Biol. 325, 317-328 (2009). (Invited review) Full text.
Here we present a mathematical model that describes the kinetics of transcriptional regulatory circuits. The model comprises the response functions of cis-regulatory modules to their transcription factor inputs, by incorporating binding site occupancy and its dependence on biologically measurable quantities. We use this model to simulate gene expression, to distinguish between cis-regulatory execution of “AND” and “OR” logic functions, rationalize the oscillatory behavior of certain transcriptional auto-repressors and to show how linked subcircuits can be dealt with.
Sorin Istrail, Smadar Ben-Tabou de-Leon and Eric. H. Davidson, The regulatory genome and the computer, Dev. Biol.310, 187-195, (2007). Full text.
Here we consider the operating principles of the genomic computer, the product of evolution, in comparison to those of electronic computers. For example, in the genomic computer intra-machine communication occurs by means of diffusion (of transcription factors), while in electronic computers it occurs by electron transit along pre-organized wires. There follow fundamental differences in design principle in respect to the meaning of time, speed, multiplicity of processors, memory, robustness of computation and hardware and software.
Smadar Ben-Tabou de-Leonand Eric H. Davidson, Gene regulation: Gene control network in development, Annu. Rev. Biophys. Biomol. Struct. 36, 191-212, (2007). (Invited review). PDF.
In this review we use the gene regulatory network that governs endomesoderm specification in the sea urchin embryo to demonstrate the salient features of developmental gene regulatory networks and illustrate the information processing that is done by the regulatory sequences.
Smadar Ben-Tabou de-Leon and Eric H. Davidson, Deciphering the underlying mechanism of specification and differentiation: The sea urchin gene regulatory network. Science STKE 2006, pe47 (2006). NCBI.
In this prespective we overview the general design principles of gene regulatory networks for animal development using the sea urchin gene regulatory network as an example.
Dr. Smadar Ben-Tabou de-Leon
Developmental gene regulatory networks and their evolution
Dr. Tzvia Gildor
Comparative studies of transcription expression dynamics
Dr. Modi Roopin
Regulation and evolution of developmental processes: VEGF-induced skeletogenesis in sea urchin embryo
Lama Khalaily, M.Sc. student
VEGF and VEGFR upstream regulation
Miri Margolis, B.Sc. student
Human VEGF effect on sea urchin skeletogenesis
How does a single cell, the fertilized egg, gives rise to tens to hundreds of cells type that self-organize to form the adult body plan?
What is the genomic program that drives embryo development, how is it encoded in the DNA and how is it executed through developmental time?
If these questions excite your imagination you are invited to apply for a M.Sc or Ph.D. positions at our lab. We address these questions by combining embryology, molecular biology, imaging, next generation sequencing, bioinformatics and mathematical modeling. The model organisms we study are sea urchin and zebrafish, two phenomenal systems for the study of embryo development.
If you are interested please send your CV and a description of your interests to:
Dr. Smadar Ben-Tabou de-Leon
Dr. Smadar Ben Tabu de Leon
Department of Marine Biology
Leon Charney School of Marine Sciences
University of Haifa,
Mt. Carmel, Haifa 3498838, Israel
School Fax: 972-4-8288267