Stability of regulators in embryonic development: epistemic implications of a changing
Internal reference number : 23/28-133
Start date : October 1st, 2023
End date : September 30, 2028
Partners
PI (spokesperson) : Pr René Rezsohazy, Université catholique de Louvain (UCLouvain), Louvain Institute of Biomolecular Science and Technology (LIBST)
Co-I 1: Pr Françoise Gofflot, Université catholique de Louvain (UCLouvain), Louvain Institute of Biomolecular Science and Technology (LIBST)
Co-I 2: Pr Frédéric Lemaigre, Université catholique de Louvain (UCLouvain), Institut de Duve (DDUV)
Co-I 3: Pr Charles Pence, Université catholique de Louvain (UCLouvain), Institut Supérieur de Philosophie (ISP)
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Aims of the Coordinated Research Project
Following the capacity to modify genes in animal genomes, developmental biology has flourished as a discipline predominantly aiming at understanding how genes and gene regulatory networks (GRNs) shape tissues, organs and organisms. Several biologists and philosophers have, however, criticized the dominance of this gene-centric view of life which tends to overemphasize the search for and intervention on genes. In that context, the teams of F. Gofflot, F. Lemaigre and R. Rezsohazy have already investigated how gene regulators (or transcription factors, TFs) integrated in GRNs control developmental processes. In line with standard practice in the field, their conclusions were often formulated using idealized GRNs as models representing the genetic control of development. We now propose to approach developmental processes by adding an additional layer of regulation after gene transcription and translation (or “hypogenetic” regulation) and to address the epistemological implications of this change in viewpoint.
At the experimental level, we will characterize a neglected layer of molecular regulations taking place at the level of proteins, namely TF stability, which is potentially a key determinant of developmental regulators' function. We will focus on Homeobox A1 (HOXA1), HOXA5, and Hepatocyte Nuclear Factor 6 (HNF6). These TFs share features that make them suitable for comparative studies: they are regulators of cell fate determination and bind to target DNA via a conserved homeodomain. Their roles have been well documented. In contrast, their modes of action have been neglected. Our goal is thus to characterize the longevity of these TFs, to determine the protein domains, interactors and molecular pathways controlling their stability, and to evaluate how modulating TFs’ stability impacts developmental processes like heart development (HOXA1), synaptogenesis (HOXA5) and hepatic cell differentiation (HNF6). We thereby intend to integrate protein stability as an underestimated determinant of GRN function. Further, together with the team of C.H. Pence, philosopher of biology, the epistemological dimension of our project will evaluate the importance of and changes in practices of model building and idealization in describing complex developmental processes. We will explore the extent to which adding this extra layer of protein regulation changes the theoretical and experimental presuppositions of the proposed biological work, investigating whether the whole is, potentially, more than the sum of its parts. In our project, philosophers and biologists will work together in the labs to invest philosophy in practice and to question the way hypotheses and conclusions are drawn by experimentalists when proposing biological models and theories.
The research team
René Rezsohazy (PI - Spokesperson)
After a Master degree in Molecular Biology (1988), I completed a PhD thesis as Research Fellow (“Aspirant”) by the FRS-FNRS (Belgium), under the supervision of Prof. J. Delcour (1993). My research project consisted in characterizing a family of mobile genetic elements from the bacterium Bacillus thuringiensis. I next moved as Postdoctoral Fellow (FEBS and EU “Biotech” grants) to the Netherlands Cancer Institute (Amsterdam), in the lab of Prof. Dr R. Plasterk. I studied mobile genetic elements in the animal model Caenorhabditis elegans (1994-1996) and identified a new family of transposons. Back from my post-doc in 1996, I was appointed as a Postdoctoral Researcher position (by the FNRS; next from UCLouvain). I joined the team of J. Picard at UCLouvain, a developmental toxicologist, who entrusted me with the task to reshape his laboratory while implementing molecular biology approaches. This was the start of my research program on HOX proteins, which I pursued as independent PI upon J. Picard's retirement in 2000. Establishing a totally new project and a new research team as a postdoc was a real challenge I successfully took up. Our team was the first to produce a recombinant mouse line at UCLouvain in full autonomy. From the early 2000s I decided to maintain a small- to mean-size research group, while taking charge of increasing teaching duties.
I obtained a permanent position in 2004 as Professor Associate at the Faculty of Sciences and Institut des Sciences de la Vie (now LIBST). I became Professor in 2009 and Full Professor in 2016. Since the earliest stages of my career I accepted to serve the university with increasing responsibilities, being successively responsible of the Biochemistry and Molecular and Cellular Biology Master program (2006-2010), Head of the Department of Biology (2008-2010), Head of the School of Biology (2010-2013), Vice-Dean of the Faculty of Sciences (2015-2020) and President of the LIBST institute (2020 -present).
Research interests and scientific achievements
The goal of our lab is to unravel key developmental mechanisms regulated by HOX proteins, a family of transcription factors that shape body plan in development and evolution. We also determine how dysregulation of those mechanisms may cause disease in humans. Our lab follows an original approach that, in contrast to other teams investigating Hox gene functions, focuses on HOX protein activity determinants and interactions. This led to the characterization of HOX protein interactomes on a proteome-wide scale.
We found that the stability and intracellular distribution of HOX proteins depend on specific modulators (e.g. PRDM14, KPC2). Obligatory partnerships (e.g. HOXA1 and PBX) for HOX' transcriptional activity were uncovered. Most significantly, we found that HOXA1 not only acts as a transcription factor but also directly modulates signal transduction by interacting with unanticipated pathway regulators, thereby expanding the known repertoire of functions associated with HOX proteins.
In the field of disease-causing mechanisms, our characterization of HOXA1 mutants found in patients determined how the mutants cause cardio-vascular malformations. In addition, we uncovered oncogenic properties for HOXA1, and our studies on the molecular biology of HOXA1 highlighted that its oncogenic properties are prone to render breast cancers refractory to hormonal treatments.
Beside my research activities in molecular developmental biology, I also devoted myself to feed some reflection in philosophy of biology and in epistemology. My first achievement in this context was to write a book with the philosopher and physicist Prof. Dominique Lambert about the concept of plasticity as necessary condition to life. I have next been involved in several meetings seminars and inter-disciplinary working groups around evolution, the principles of intelligibility of life, conceptualization of living objects. I am one of the founding members of the FNRS Contact Group in Epistemology.
Research team: One postdoc, two PhD students, two technicians
People funded by the project: Emma Dejonge, PhD student; Laure Bridoux (starting Feb. 2025), postdoc
Françoise Gofflot (Co-I)
After a Master degree in Biology (1988), I joined the team of Prof Picard (UCLouvain) to perform a thesis in Developmental Toxicology, with a IRSIA fellowship. During my phD, completed in 1994, I used the post-implantation embryo culture system to investigate the impact of a pharmaceutical agent on neural tube formation. Thanks to a EMBO fellowship, I next joined the team of Prof. Morriss-Kay working in the field of Developmental Genetics (University of Oxford), where I studied the mechanisms underlying the genesis of neural tube defects in Curly Tail mutant mice (1995-97). From 1997 to 2003, back at the UCLouvain in the team of Prof. Picard as a Research Associate, I studied Hedgehog proteins functions during embryonic development, focusing on neural tube and limb formation. From 2003 to 2008, I moved to the Mouse Clinical Institute in Strasbourg where I collaborated with Prof J. Auwerx. My work on the expression of nuclear receptors in the adult brain led to the creation of an interactive database, MousePat, and to a Cell publication. I was also involved in the characterization of transgenic mouse lines expressing an inducible form of the Cre recombinase, to be used for conditional mutagenesis in mouse. In 2008, I joined the actual Louvain Institute of Biomolecular Sciences and Technology (LIBST) at UCLouvain as Promoter of a Ulysse Incentive Grant for Mobility in Scientific Research (FNRS) to build my own team. I became associated Professor in 2010 and Professor in 2018. This position is associated with a significant teaching load and University management duties. I am particularly involved in issues related to animal experimentation, ethics and welfare, from animal housing to the implementation of procedures
Main scientific achievements and research interests
My current interest is focused on deciphering the functions and mode of action of Hox genes/proteins in the late stages of central nervous system formation in the mouse. In 2014, we provided the first detailed quantitative and neuroanatomical characterisation of the expression of the 39 Hox genes in the adult mouse brain. Our data highlighted the importance of Hox genes well beyond their role as patterning genes, suggesting functional relevance in the late processes of neural circuit formation, maturation and plasticity. As further study of Hox gene functions at postnatal stages requires a mouse model to target gene inactivation around birth, we developed procedures that allow robust recombination of floxed alleles at perinatal stages in the brain, which is known to be more problematic to target. We then selected Hoxa5, a member of the Hox gene family that plays a critical role in the successive stages of central nervous system formation, for further analysis. Five years ago, our team was the first to demonstrate that HOXA5 is functional in the hindbrain during the first postnatal weeks, where it regulates key players involved in synapse function. Importantly, some of the genes regulated by HOXA5 are involved in the susceptibility to develop autism spectrum disorders in humans or mice. Our latest data showed that mutant mice with postnatal inactivation of HOXA5 also show deficits in autism-related behaviours, supporting the hypothesis of a correlation between HOXA5 and this neurodevelopmental disorder. Based on the literature, we were able to extend our observations to other HOX proteins, and suggest that several of these transcription factors are involved in late phases of central nervous system formation, including synapse assembly and maturation. Our findings thus not only contribute to a better understanding of Hox genes late functions but also provide the opportunity to identify and understand the neurobiological pathways that are responsible for the onset of neurodevelopmental disorders.
Reserach team: three PhD students, two technicians
People funded by the project: Manel Berkemal, PhD Student
Frédéric Lemaigre (Co-I)
After obtaining an MD degree (1986) at the UCLouvain, I started a career in fundamental research. I joined the team of Prof. G. Rousseau (UCLouvain) to investigate the control of eucaryotic gene expression, focusing on hormonal and tissue-specific regulations. With support of a NIH fellowship, I then moved to Michael R. Green's lab (University of Massachusetts) for a post-doctoral stay (1991-1992) to study structure-function relationships of ATF transcription factors. Upon my return in Belgium, G. Rousseau offered me the opportunity to resume my research on liver-specific gene expression in his team with full intellectual freedom and funding support. This enabled me to obtain a permanent and independent position at the Belgian National Fund for Scientific Research (1994) and subsequently to build my team at UCLouvain and de Duve Institute. My research then evolved from molecular biology of transcription factors to the investigation of cell differentiation and tissue morphogenesis in development and cancer. In parallel to my research career, I obtained a Professor position at the UCLouvain medical school (2002). This position is associated with a significant teaching load (molecular biology and biochemistry) and University management duties, and with various services to the scientific community at the national and international level.
Main scientific achievements and research interests
My current laboratory's goal is to determine how gene regulatory networks drive cell differentiation and tissue morphogenesis, and how deregulation of such networks contributes to disease. The work is focused on gene regulatory mechanisms in liver and pancreas. In this context, we discovered the family of ONECUT transcription factors (HNF6, OC-2, OC-3); we showed how these factors are essential for development of hepatocytes and cholangiocytes in liver; and for development of endocrine and exocrine cells in pancreas. Beyond our work on ONECUT factors, we further identified molecular pathways essential for hepatic cell differentiation, and uncovered key mechanisms regulating bile duct development. In diseased liver, we found how dysregulated gene networks promote dedifferentiation and tumor progression in hepatocellular carcinoma and cholangiocarcinoma. In pancreas, we found how inflammation-driven gene networks perturb differentiation and initiate pancreatic cancer.
Overall, our research impacts cell therapy of liver disease and diabetes, diagnosis of liver malformations, understanding the mechanisms of liver regeneration, and characterization of early stages of liver and pancreatic cancer. This work has earned me recognition among the 2% of the world's top developmental biologists by the Stanford University in 2021.
Reserach team:
People funded by the project: Romane Schils, PhD Student
Charles Pence (Co-I)
I received an A.B. in Philosophy from Princeton University (2007), followed by a M.A. in Philosophy and a Ph.D. in History and Philosophy of Science from the University of Notre Dame (2014), where I was a Lilly Graduate Presidential Fellow. My thesis project explored the historical development and contemporary implications of the concept of “chance” in evolutionary theory, a research topic to which I still contribute. I went on to an Assistant Professor position at Louisiana State University in Baton Rouge, Louisiana (2014-2018), where I was Director of the LSU Ethics Institute. I took a position at UCLouvain in the Institut supérieur de Philosophy and the Faculty of Philosophy, Arts, and Letters in 2018. In 2022, I received tenure and was elected a member of the inaugural class of the Collegium (Young Academy) of the Académie royale de Belgique. Since my arrival at UCLouvain, I have maintained a small research group, averaging around two post-doctoral fellows and one to two doctoral students.
Throughout my career, I have been extensively involved in local and international scientific service, including co-editing a journal, serving on numerous committees for scientific societies, and serving locally as the director of our research center (Center for the Philosophy of Science and Society, or CEFISES).
Research interests and scientific achievements
I am a philosopher and historian of the life sciences, with a particular focus on evolutionary theory. In my work, this has led to contributions to two important areas, as well as the development of two particular sets of tools.
First, my work has been extensively grounded in the history of biology. I have published on Darwin (including an encyclopedia article on his life in the Internet Encyclopedia of Philosophy) and the first several decades of evolutionary theory, with a focus on the development of the mathematical methods of statistics and the concepts of chance that grounded their use (e.g., the 2022 monograph The Rise of Chance in Evolutionary Theory, Elsevier). This has led to a larger focus on the philosophical context of this scientific work, including work on 19th-century British philosophy of science (e.g., a 4-volume primary source collection, Scientific Methodology in Nineteenth-Century Britain, to appear with Routledge).
Secondly, I have focused on the relevance of these historical insights for contemporary philosophy of biology and contemporary biological practice (e.g., The Causal Structure of Evolutionary Theory, Cambridge Elements, Cambridge UP). This has led to work on the nature of explanations involving natural selection in general, as well as particular interventions in biological practice, including work on divergence time estimation and on animal behavior.
Both my historical and contemporary work, then, has been informed by use of the digital humanities. My lab is one of the first groups to extensively deploy these methods in the philosophy of biology, and we have maintained a publicly accessible tool, Sciveyor, for analyzing the scientific journal literature, for over a decade. This work has led to a specialization in text mining and the emergence of our group as something of a “technique lab” for others: current projects to which we are contributing include work in causal specificity, scientific progress, the philosophy of mathematics, and cladistics.
Finally, I am increasingly involved in the analysis of the implications of science for society, including ethics (such as our ongoing H2020 project on the ethics of organoids), but more broadly including the use and role of scientific concepts as they leave the scientific community (e.g., FNRS PDR on the concept of biodiversity, now also the basis of my four-year project at the Académie royale). These questions of scientific communication and engagement, as well as the transfer of scientific knowledge beyond the ivory tower, have led to significant engagement with community members and non-university stakeholders.
Research team:
People funded by the project: Azat Garaev, PhD student
Theses defended in the context of the Coordinated Research Project
Activities organised as part of the Coordinated Research Project
Publications in connection with the Coordinated Research Project
Contact point in UCLouvain
Pr René Rezsohazy, Principal Investigator (spokesperson/coordinator), Université catholique de Louvain (UCLouvain), Louvain Institute of Biomolecular Science and Technology (LIBST), E-mail: rené Rezsohazy