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Neurobiology of nuclear hormone receptors

Neurobiology of nuclear hormone receptors

SUBGROUP LEADER

Wojciech KREZEL

Whereas vitamin A is best known for its critical role during embryonic development and visual cycle (documented by 3 Nobel prizes), its post-natal activities, including in neuroprotection, modulation of neurotransmission and synaptic plasticity only start being discovered and understood. Our goal is to decipher the highly diverse functions of vitamin A, its active derivatives (retinoic acids), and the corresponding nuclear receptors (RARs/RXRs), in neural development, aging, and in stem cell control. Our studies of specific retinoid receptors and bioactive metabolites in control of diverse biological processes should contribute to a better understanding of the mechanisms underlying development and function of specific cell types and relevant neural circuits. We also investigate the therapeutic potential of specific retinoids in neurological and psychiatric diseases.

To address these questions, we use genetic, pharmacological or behavioral mouse models of specific diseases, as well as CRISPR- and viral-based approaches to control gene expression. Our mechanistic studies are guided by combination of genomic, proteomic and metabolomic data from clinics and mouse models. In collaboration with experts in chemistry we also develop new tools to study biological processes in vivo (e.g. click chemistry, novel RXR agonists). We have shown that fine-tuning of retinoic acid activity depends on its spatiotemporal patterns of synthesis (by retinol and retinaldehyde dehydrogenases) and catabolism (by CYP26 enzymes).

Our current focus relates to the role of retinoids in brain physiology and pathology, with a particular interest in basal ganglia and dopaminergic signaling, whose dysfunctions are associated with several neuropsychiatric disorders. These studies take advantage of murine models relevant to neurodevelopmental disorders, Parkinson and Huntington diseases, and depression. We also investigate mechanisms of glial cell development and biology to elaborate regenerative medicine approaches in multiple sclerosis.  A long-term goal is to understand the mechanisms underlying these disorders, and develop new strategies or compounds for their prevention or therapy.

 

 

Current projects

Role of retinoids in development and pathophysiology of the dopaminergic system

Even subtle alterations in dopaminergic signaling may affect brain functions, and may underlie various neuropsychiatric diseases. Our ongoing projects are focused on development and functions of the dopaminergic system in basal ganglia including striatum, a brain region important for control of motor, affective and cognitive functions. The goal is to understand how discrete developmental events contribute to physiological diversity in cognitive performance, or affective susceptibility to stress, and understand the neurodevelopmental basis of neurologic diseases. We are also testing known and newly characterized retinoids for treatment of such brain disorders in relevant animal models.

 

Cell fate analyses in mouse brain : an engineered reporter gene, inserted in the mouse genome, allows lineage analysis of cells expressing a gene of interest

 

Retinoids in neurodegenerative diseases

Recent data point to beneficial effects of specific retinoids or retinoid receptors in distinct neurodegenerative diseases. We investigate mechanisms underlying such activities, focusing for example on control of mitochondrial functions and calcium signaling in rare neurodegenerative diseases including Huntington disease or MCOPS12 (microphtalmia, syndromic 12 - a rare disease for which causative mutations in RAR beta have been identified), or cell differentiation and neuroinflammation in the context of regenerative medicine in multiple sclerosis. Such studies are guided by genomic and epigenetic analyses of existing and new genetic mouse models relevant for those diseases. We have also invested in innovative techniques applied to these mouse models to obtain single cell resolution in our studies.

 

Virus-mediated deletion of RAR beta in adult mouse striatum : lower panels show absence of RAR beta protein in striatal cells, whereas a reporter EGFP gene allows to identify cells in which the corresponding locus remains active (From Ciancia et al., 2022)

New tools for studies of biological processes and drug development

A recurrent challenge in modern biology is to integrate into a more global picture molecular, cellular and functional determinants of a given biological process. In collaboration with experts in synthetic, analytical and biological chemistry, we elaborate tools for multilevel studies of small bioactive molecules or circulating drugs in living organisms. The key to such approaches are rapid and irreversible chemical reactions ("click chemistry"), which can be carried out in a complex biological environment.  A prototypic example is the development of click chemistry reactions in the living organism, which we showed useful for rapid inactivation and renal elimination of a purpose-designed drug. This work paves the way for new strategies in drug design and studying of endogenous metabolic or signalling processes.

 

An example of cell-type specific chemoprobe reaction

Collaborations and networks

Vito Antonio BALDASSARRO (ORCID ID: 0000-0003-1020-4261) and Laura CALZA  (ORCID ID: 0000-0002-4426-8477), Department of Veterinary Medical Science, Department of Pharmacy and BioTechnology, University of Bologna, Italy) – Multiple sclerosis, glial cell biology, endocrinology

François FENAILLE, ORCID ID: 0000-0001-6787-4149 , CEA, Frédéric Joliot Institute for Life Sciences, Paris, France – Analytical chemistry 

Emmanuel HAFFEN, ORCID ID: 0000-0002-4091-518X, CHU de Besançon, Université de Franche-Comté, Laboratoire de recherche Intégrative en Neuroscience & Psychologie Cognitive, Besançon, France – Psychiatry, clinical and experimental neurobiology

Angel de LERA, ORCID ID: 0000-0001-6896-9078, Universidade de Vigo, Vigo, Galicia, Spain – Chemistry of retinoids

Jacques MICHAUD, ORCID ID: 0000-0002-9912-0293, CHU Sainte-Justine Research Center, Department of Pediatrics, Department of Neurosciences, Université de Montréal, Québec, Canada – Clinical and experimental studies of neurodevelopmental diseases, rare diseases

Shin-Ichi MURAMATSU, ORCID ID: 0000-0002-3185-7790, Jichi Medical University, The Institute of Medical Science, The University of Tokyo – Gene therapy using viral vectors, dopamine signaling, Parkinson disease

Olivier POCH, ORCID ID: 0000-0002-7134-3217, Complex Systems and Translational Bioinformatics, iCUBE, University of Strasbourg, France – Bioinformatics & big data

Natacha ROCHEL-GUIBERTEAU, ORCID ID: 0000-0002-3573-5889, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Strasbourg, France – Structural biology of nuclear hormone receptors

Verdon TAYLOR, ORCID ID: 0000-0003-3497-5976, University of Basel, Department of Biomedicine, Basel, Switzerland – Neurodevelopmental and neurodegenerative diseases, human iPSCs

Alain WAGNER, ORCID ID: 0000-0003-3125-601X, University of Strasbourg, Laboratory of Design and Application of Bioactive Molecules, Strasbourg, France – Design of bioactive molecules, chemical synthesis

Julianne WINKELMAN, ORCID ID: 0000-0003-2667-9691, Helmholtz Zentrum München, Institute of Neurogenomics, Neuherberg, Germany – Clinical and experimental research on neurologic diseases, neurogenetics


Job offers

Awards and recognitions

Wojciech Krezel was appointed USIAS (University of Strasbourg Institute for Advanced Studies) Fellow (2018)

Anna Podlesny, a former PhD student, received a “Diamond Grant” from Poland Ministry of Education (2013)

Resources

"Cure MPOCS12": a registered nonprofit organization dedicated to improve the lives of children and families affected by the MCOPS12 syndrome, caused by mutations in RAR beta

Funding and partners

* Current grants & contracts include:

Agence Nationale de la Recherche (ANR): "ROLinMAP" project (Novel bioorthogonal chemistry approaches to study biology of small molecules)

ERA-Net network & grant: "RAinRARE" (Retinoid signaling and rare diseases)

University of Strasbourg Institute of Advanced Studies (USIAS) grant

Fondation pour l'aide à la recherche sur la sclérose en plaques (ARSEP)

 

* Previous grants also included ANR, European (ERA-Net), University of Strasbourg, or Foundation (Fondation pour la Recherche Médicale, Fondation de France, France Parkinson, etc) contracts

 

* Various fellowships have been obtained to support our PhD students (Life Sciences Doctoral School, IGBMC PhD program, IMCBio Research Doctoral School, Joint grants with foreign Universities, various Foundations for extension/4th year of PhD studies, etc)

Publications