Clicky

menu

Gene Regulation in Development and Evolution

Head of the Lab: Dr. Smadar Ben Tabou deLeon

 Lab overview

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.

skeletogenesisMajor projects in the lab where we are currently recruiting students 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 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.hvegf
  • 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.

fig 1-1

Fresh from our lab

2017

  • Parallel embryonic transcriptional programs evolve under distinct constraints and may enable morphological conservation amidst adaptation, Assaf Malik, Tsvia Gildor, Noa Sher, Majed Layous and Smadar Ben-Tabou de-Leon, Dev. Biol. In press. In this paper we study conservation and change in gene expression patterns between two closely related sea urchin species in a transcriptome level. We discovered that developmental and housekeeping gene expression is dynamic and conserved but the kinetic behavior or the two sets is different. Divergence is observed in 35% of the genes probably due to drift, but also adaptation to local environmental conditions. The position of the stage of highest conservation (phylotypic stage) is at mid-developmental stage for developmental genes (hourglass pattern) while the conservation of housekeeping genes keeps increasing with developmental time (funnel pattern). Thus, different gene sets seem to evolve under different constraints that result with different conservation patterns, which might allow embryos to conserve their morphology while adapting to local changes. http://www.sciencedirect.com/science/article/pii/S0012160617303421
  • Regulatory heterochronies and loose temporal scaling between sea star and sea urchin regulatory circuits, Tsvia Gildor, Veronica Hinman and Smadar Ben-Tabou de-Leon, Int. J. Dev. Biol., 2017;61(3-4-5):347-356. doi: 10.1387/ijdb.160331sb. In this paper we compare the expression dynamics of regulatory genes between two echinoderm embryos that shared a common ancestor about 500 million years ago: the sea urchin and the sea star. We find that despite the large evolutionary distance and morphological differences between the embryos there are only mild heterochronies between the expression dynamics of regulatory genes in all embryonic territories. This finding emphasize the strong developmental constraints that do not permit evolutionary change of the expression dynamics of core developmental regulatory genes over 500 million years of parallel evolution. http://www.ijdb.ehu.es/web/paper/160331sb/regulatory-heterochronies-and-loose-temporal-scaling-between-sea-star-and-sea-urchin-regulatory-circuits

2016

  • Mature maternal mRNAs are longer than zygotic ones and have complex degradation kinetics in sea urchin, Tsvia Gildor, Assaf Malik, Noa Sher and Smadar Ben-Tabou de-Leon, Developmental Biology, 2016 press. In this paper we discover that the maternal mRNAs are longer  than zygotic mRNA in sea urchin embryos, specifically, their coding sequences and 3'UTR. This indicates differential gene usage and regulation of the maternal transcripts. We also measure the turn-over rates of maternal mRNAs due to maternal and zygotic degradation mechanisms and learn that they are not correlated. This indicates that the maternal and zygotic degradation mechanisms are independent and probably relay on different regulatory seuqences in the 3'UTRs of the maternal transcripts.   http://www.sciencedirect.com/science/article/pii/S0012160615303857
  • Robustness and accuracy in sea urchin developmental gene regulatory networks, Smadar Ben-Tabou de-Leon, Frontiers in genetics (2016). In this perspective I propose that the use of specific architectures by the sea urchin developmental regulatory networks enables the robust control of cell fate decisions. http://journal.frontiersin.org/article/10.3389/fgene.2016.00016/full
  • Quantitative Developmental Transcriptomes of the Mediterranean sea urchin, Paracentrotus lividus Tsvia Gildor, Assaf Malik, Noa Sher, Linor Avraham and Smadar Ben-Tabou de-Leon, Marine Genomics, 25, 89-94, (2016). In this paper we study the developmental transcriptomes of P. lividus at seven developmental time points, from the fertilized egg to the prism stage. This study portrays the rich patterns of temporal genes expression that drive sea urchin embryogenesis and provide and essential recourse for the sea urchin community. http://www.sciencedirect.com/science/article/pii/S1874778715300556

2015

  • Comparative Study of Regulatory Circuits in Two Sea Urchin Species Reveals Tight Control of Timing and High Conservation of Expression Dynamics. Tsvia Gildor and Smadar Ben-Tabou de-Leon, Plos Genetics (2015) In this paper we detect striking interspecies conservation of the expression dynamics of regulatory and differentiation genes between two sea urchin species that are geographically and genetically distant. This study demonstrates the amazing ability of gene regulatory networks to conserve expression dynamics over 50 million years of evolution. http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005435

Join us

We are recruiting M.Sc. and Ph.D. students. If you are interested please send your CV and research interests to:  sben-tab@univ.haifa.ac.il

For further review of our current research projects please see Research below.
For a review of the major results of our previous work, please see Publication.
 
 

d71_9263

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.

hvegf

 

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.

fig 1-1

 

The effect of pollution and global warming on gene regulation and development of the sea urchin embryo

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.

sw_vs_asw_16_vs_18c_7-8-2013

 

Lab publications

  1. Mature maternal mRNAs are longer than zygotic ones and have complex degradation kinetics in sea urchin, Tsvia Gildor, Assaf Malik, Noa Sher and Smadar Ben-Tabou de-Leon, Developmental Biology, in  press. In this paper we discover that the maternal mRNAs are longer  than zygotic mRNA in sea urchin embryos, specifically, their coding sequences and 3'UTR. We also find that the turn-over rates due to maternal and zygotic degradation mechanisms are not correlated.   http://www.sciencedirect.com/science/article/pii/S0012160615303857
  2. Robustness and accuracy in sea urchin developmental gene regulatory networks, Smadar Ben-Tabou de-Leon, Frontiers in genetics, In press. In this perspective I propose that the use of specific architectures by the sea urchin developmental regulatory networks enables the robust control of cell fate decisions. http://journal.frontiersin.org/article/10.3389/fgene.2016.00016/full
  3. Quantitative Developmental Transcriptomes of the Mediterranean sea urchin, Paracentrotus lividus, Tsvia Gildor, Assaf Malik, Noa Sher, Linor Avraham and Smadar Ben-Tabou de-Leon, Marine Genomics, 25, 89-94, (2016). In this paper we study the developmental transcriptomes of P. lividus at seven developmental time points, from the fertilized egg to the prism stage. This study portrays the rich patterns of temporal genes expression that drive sea urchin embryogenesis and provide and essential recourse for the sea urchin community. http://www.sciencedirect.com/science/article/pii/S1874778715300556
  4. Comparative Study of Regulatory Circuits in Two Sea Urchin Species Reveals Tight Control of Timing and High Conservation of Expression Dynamics, Tsvia Gildor, and Smadar Ben-Tabou de-Leon, Plos Genetics (2015) In this paper we detect striking interspecies conservation of the expression dynamics of regulatory and differentiation genes between two sea urchin species that are geographically and genetically distant. This study demonstrates the amazing ability of gene regulatory networks to conserve expression dynamics over 50 million years of evolution. http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1005435

Previous related publications

  1. 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.  

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

20150607_104745
 
Dr. Smadar Ben-Tabou de-Leon
Senior Lecturer
Developmental gene regulatory networks and their evolution
Dr. Tzvia Gildor
Lab Manager

Comparative studies of transcription expression dynamics

Dr. Modi Roopin
Post Doctorat
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, M.Sc. student
The regulation of sea urchin tubular spicule cord formation by VEGF signaling and cytoskeletal remodeling
 
Majed Layous, M.Sc. student
The mechanisms activated by hypoxic condition to regulate VEGF expression and skeletal patterning

Join us!

  • 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

Email: sben-tab@univ.haifa.ac.il

 

Contact Us

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

Email: sben-tab@univ.haifa.ac.il

1555340_588893531219847_8925962954145226296_n 10600601_588659531243247_8775004140942780566_n

Scientists night September 2014

peres viosit 

Shimon Peres visit October 2014


Lab Warming 27/11/2013

"