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Séminaire - Séminaire Bx Neurocampus mensuel: Wojciech KrezelA vitamin for good development and aging

Abstract :

Seconde conférence mensuelle

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Assistez aux… Bordeaux Neurocampus PhD Seminar Series" / Every first Friday of the month

All-trans retinoic acid (ATRA, an active form of vitamin A) is known as a potent inducer of neuronal differentiation in various systems including cell lines and neuronal precursor cells, in vitro and in vivo. Despite these observations, the neuronal subtypes arising during ATRA-induced differentiation, their integration into neuronal circuits, is less understood. Little is known also about postnatal roles of ATRA in control of brain functions, although several studies suggest that such functions may occur throughout life.
The striatum offers a particularly interesting model to study both developmental and postnatal functions of RA signaling, as it is a site of expression of only few retinoid receptors, binding proteins or metabolic enzymes and it is critically involved in control of diverse behavioral activities through distinct neural circuits. Striatonigral and striatopallidal GABAergic medium spiny neurons (MSNs) form the two major output pathways of the striatum and display significant molecular differences including specific expression of dopamine Drd1 and Drd2 receptors, respectively. 

Coordinated activity of these projection neurons is critical for normal striatal functions, as revealed by the numerous motor, cognitive and affective abnormalities associated with their imbalanced signaling in neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, or psychiatric disorders like schizophrenia or depression.

Our studies reveal that a single receptor, RARβ, has different functions in the embryonic and postnatal striatum. Whereas during embryonic development, by modulating FGF signaling it controls differentiation of a subpopulation of Drd1-expressing MSNs, during postnatal life it is required for homeostasis of Drd2-expressing neurons. In consequence, RARβ-null mutant mice display panoply of behavioral deficits which may be directly relevant to some neurologic disease. Whereas RARb-dependent control of striatal development and functions may reflect activities of ATRA, we have recently identified 9-cis-13,14-dihydro-retinoic acid (9cDHRA) as the first retinoid acting as an endogenous agonist of retinoid X receptors (RXRs). Our pharmaco-genetic analyses indicate that RXRs mediate 9cDHRA signaling in control of cognitive and affective behaviors by modulation of CNS physiology.

Selected publications

Niewiadomska-Cimicka A, Krzyzosiak A, Ye T, Podlesny-Drabiniok A, Dembele D, Dolle P, Krezel W (2016) Genome-wide analysis of RARβ transcriptional targets in mouse striatum links retinoic acid signaling with Huntington’s disease and other neurodegenerative disorders. Mol Neurobiol 2016

Rataj-Baniowska M, Niewiadomska-Cimicka A, Paschaki M, Szyszka-Niagolov M, Carramolino L, Torres M, Dollé P, Krezel W (2015) Retinoic acid receptor beta controls development of striatonigral projection neurons through FGF- and Meis1-dependent mechanisms. J Neurosci 35 (43):14467-14475.

Ruhl R, Krzyzosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, Wietrzych-Schindler M, Alvarez S, Szklenar M, Nagy L, de Lera AR, Krezel W (2015) 9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice. PLoS Genet 11:e1005213.

Wietrzych-Schindler M, Szyszka-Niagolov M, Ohta K, Endo Y, Perez E, de Lera AR, Chambon P, Krezel W (2011) Retinoid x receptor gamma is implicated in docosahexaenoic acid modulation of despair behaviors and working memory in mice. Biol Psychiatry 69 (8):788-794.

Krzyzosiak A, Szyszka-Niagolov M, Wietrzych M, Gobaille S, Muramatsu S, Krezel W (2010) Retinoid x receptor gamma control of affective behaviors involves dopaminergic signaling in mice. Neuron 66:908-920.

Scientific focus :

1997, PhD in molecular genetics, Université Louis Pasteur, Strasbourg, France;
1998-2001, post-doctoral training in behavioural neurobiology and electrophysiology, Cardiff University, Wales, UK;
2001-2005, setting-up of behavioural platform at Mouse Clinical Institute (MCI) and research scientist at IGBMC;
2006, CR1 at INSERM and HDR in neuroscience at the University of Strasbourg;
since 2012 research director (DR2) at INSERM carries out research at IGBMC studying role of nuclear hormone receptors in brain development and physiology.