From stem cells to prion signalling

Abstract

A strategy based upon the introduction of an adenovirus-SV40 plasmid into multipotential cells was designed to immortalize clones displaying properties of lineage stem cells. The murine 1C11 cell line behaves as a neuroepithelial progenitor. Upon appropriate induction, almost 100 % of 1C11 precursor cells develop neurite extensions and convert into either serotonergic or noradrenergic neurons. The two mutually exclusive neuronal programs are autoregulated by serotonergic or adrenergic receptors. PrP c is constitutively expressed by 1C11 cells. Antibody-mediated cross-linking of PrP c promotes the dephosphorylation of the tyrosine kinase Fyn associated to a Fyn kinase activation. The coupling of PrP c to Fyn is dependent on caveolin-1. It is restricted to the fully differentiated serotonergic or noradrenergic cells and occurs mainly at neurites. Thus, PrP c may represent a signal transduction protein which may fine-tune neuronal functions. Since the 1C11 stem cell supports prion replication, it may provide a tool to investigate whether PrP Sc accumulation interferes with PrP c signalling activity. To cite this article: O. Kellermann et al., C. R. Biologies 325 (2002) 9-15. © 2002 Académie des Sciences/Éditions scientifiques et médicales Elsevier SAS lineage stem cells / signal transduction / prion / neuronal differentiationRésumé -Une cellule souche neuronale pour étudier le rôle fonctionnel de la protéine prion. L'introduction d'un plasmide immortalisant dans des cellules multipotentielles, a permis d'obtenir des cellules souches des différents lignages. La lignée murine 1C11 a les propriétés d'un précurseur neuroectodermique bipotentiel qui, après induction, acquiert l'ensemble des fonctions des neurones sérotoninergiques ou catécholaminergiques. Les programmes de différenciation sont mutuellement exclusifs et régulés par des autorécepteurs bioaminergiques. Le clone 1C11 exprime naturellement la protéine prion (PrP c ). La ligation de la PrP c avec des anticorps anti-PrP provoque une activation de la tyrosine kinase Fyn. Ce couplage, qui dépend d'une interaction PrP c /cavéoline, n'est détecté que dans les cellules ayant acquis un phénotype sérotoninergique ou noradrénergique complet. Il implique principalement les molécules de PrP c localisées sur les neurites. La PrP c pourrait donc jouer un rôle dans le réseau des voies de transduction qui contrôlent l'homéostasie des neurones. La lignée 1C11 est infectable par les prions, elle constitue un nouveau modèle pour comprendre comment l'accumulation de PrP Sc interfère avec le rôle fonctionnel de la PrP c . Pour citer cet article : O.

NADPH oxidase and extracellular regulated kinases 1/2 are targets of prion protein signaling in neuronal and nonneuronal cells

“…Actually, in these cells, PrP C was shown not to physically and functionally interact with caveolin. In contrast, in fully differentiated serotonergic or noradrenergic progenies, which express the overall neurotransmitter-associated functions of bioaminergic neurons, PrP C -caveolin interaction and Fyn activation were shown to occur preferentially at neurites (12,28). Therefore, in these bioaminergic neuronal cells, one can imagine a localization of PrP C , caveolin and Fyn within specialized microdomains known to concentrate other signaling effectors (29,30).…”

Modulation of Serotonergic Receptor Signaling and Cross-talk by Prion Protein*

“…Noticeably, we previously highlighted that the implementation of a complete neuronal differentiation program is strictly required in the 1C11 cell line for the onset of a functional PrP C -caveolin-Fyn signaling complex (12). Furthermore, this complex involves PrP C molecules located on cell processes and most likely on the varicosities of the neurites (12,13). Beyond this neuronal specificity of PrP C coupling, we assigned a more ubiquitous signaling activity to PrP C , notably in 1C11 progenitor cells, independent from caveolin (11).…”

“…It may relate to the proper structural organization of the partners within subcellular microdomains. Noticeably, the PrP C -Fyn coupling occurs on the neurites of 1C11-derived neuronal progenies where bioaminergic receptors are most likely localized (13). We assume that the PrP C -dependent signaling activity may contribute to cell homeostasis and take part to the fine-tuning of neuronal and neurotransmitter-associated functions, notably in 1C11 5-HT fully differentiated serotonergic cells.…”

Ageing and exposure to oxidative stressin vivodifferentially affect cellular levels of PrPcin mouse cerebral microvessels and brain parenchyma

“…This study shows that not only is PrP c elevated in both brain parenchymal cells, and microvessels with normal ageing, and hyperoxia in mice, but that the microvascular compartment exhibits a PrP c profile that differs significantly from that of the brain parenchyma. In addition, microvascular PrP c exhibits a response to hyperoxia that that of copper-binding protein [16], antioxidant [17] exhibiting superoxide-like activity [18], a component of signal transduction pathways [19], and a regulator of cell proliferation and survival [20]. The present study clearly shows (i) the ability of hyperoxia-induced oxidative stress to elevate cellular levels of PrP c in the C57Bl/6J mouse brain, and (ii) that cellular expression or degradation of PrP c increases or decreases, respectively, with advancing age.…”

“…The normally occurring cellular form of prion protein (PrP c ) has been assigned numerous functions, including that of copper‐binding protein [16], antioxidant [17] exhibiting superoxide‐like activity [18], a component of signal transduction pathways [19], and a regulator of cell proliferation and survival [20]. The present study clearly shows (i) the ability of hyperoxia‐induced oxidative stress to elevate cellular levels of PrP c in the C57Bl/6J mouse brain, and (ii) that cellular expression or degradation of PrP c increases or decreases, respectively, with advancing age.…”