The dual developmental origin of spinal cerebrospinal fluid-contacting neurons gives rise to distinct functional subtypes.

Chemical and mechanical cues from the cerebrospinal fluid (CSF) can affect the development and function of the central nervous system (CNS). How such cues are detected and relayed to the CNS remains elusive. Cerebrospinal fluid-contacting neurons (CSF-cNs) situated at the interface between the CSF and the CNS are ideally located to convey such information to local networks. In the spinal cord, these GABAergic neurons expressing the PKD2L1 channel extend an apical extension into the CSF and an ascending axon in the spinal cord. In zebrafish and mouse spinal CSF-cNs originate from two distinct progenitor domains characterized by distinct cascades of transcription factors. Here we ask whether these neurons with different developmental origins differentiate into cells types with different functional properties. We show in zebrafish larva that the expression of specific markers, the morphology of the apical extension and axonal projections, as well as the neuronal targets contacted by CSF-cN axons, distinguish the two CSF-cN subtypes. Altogether our study demonstrates that the developmental origins of spinal CSF-cNs give rise to two distinct functional populations of sensory neurons. This work opens novel avenues to understand how these subtypes may carry distinct functions related to development of the spinal cord, locomotion and posture

Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

International audienceBACKGROUND: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome. CONCLUSION/SIGNIFICANCE: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

An Integrin-Dependent Role of Pouch Endoderm in Hyoid Cartilage Development

Pharyngeal endoderm is essential for and can reprogram development of the head skeleton. Here we investigate the roles of specific endodermal structures in regulating craniofacial development. We have isolated an integrinα5 mutant in zebrafish that has region-specific losses of facial cartilages derived from hyoid neural crest cells. In addition, the cranial muscles that normally attach to the affected cartilage region and their associated nerve are secondarily reduced in integrinα5(−) animals. Earlier in development, integrinα5 mutants also have specific defects in the formation of the first pouch, an outpocketing of the pharyngeal endoderm. By fate mapping, we show that the cartilage regions that are lost in integrinα5 mutants develop from neural crest cells directly adjacent to the first pouch in wild-type animals. Furthermore, we demonstrate that Integrinα5 functions in the endoderm to control pouch formation and cartilage development. Time-lapse recordings suggest that the first pouch promotes region-specific cartilage development by regulating the local compaction and survival of skeletogenic neural crest cells. Thus, our results reveal a hierarchy of tissue interactions, at the top of which is the first endodermal pouch, which locally coordinates the development of multiple tissues in a specific region of the vertebrate face. Lastly, we discuss the implications of a mosaic assembly of the facial skeleton for the evolution of ray-finned fish

Antihypertensive Drug Guanabenz Is Active In Vivo against both Yeast and Mammalian Prions

Background: Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans. [br/] Methodology/Principal Findings: Here we report the discovery of the in vivo antiprion activity of Guanabenz (GA), an agonist of a2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast prions using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrPSc clearance in a cell-based assay. These effects are very specific as evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on a2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prolonging slightly but significantly the survival of treated animals. [br/] Conclusion/Significance: GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based diseases. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases

Neuronal differentiation of hair-follicle-bulge-derived stem cells co-cultured with mouse cochlear modiolus explants

Stem-cell-based repair of auditory neurons may represent an attractive therapeutic option to restore sensorineural hearing loss. Hair-follicle-bulge-derived stem cells (HFBSCs) are promising candidates for this type of therapy, because they (1) have migratory properties, enabling migration after transplantation, (2) can differentiate into sensory neurons and glial cells, and (3) can easily be harvested in relatively high numbers. However, HFBSCs have never been used for this purpose. We hypothesized that HFBSCs can be used for cell-based repair of the auditory nerve and we have examined their migration and incorporation into cochlear modiolus explants and their subsequent differentiation. Modiolus explants obtained from adult wild-type mice were cultured in the presence of EF1α-copGFP-transduced HFBSCs, constitutively expressing copepod green fluorescent protein (copGFP). Also, modiolus explants without hair cells were co-cultured with DCX-copGFP-transduced HFBSCs, which demonstrate copGFP upon doublecortin expression during neuronal differentiation. Velocity of HFBSC migration towards modiolus explants was calculated, and after two weeks, co-cultures were fixed and processed for immunohistochemical staining. EF1α-copGFP HFBSC migration velocity was fast: 80.5 ± 6.1 μm/h. After arrival in the explant, the cells formed a fascicular pattern and changed their phenotype into an ATOH1-positive neuronal cell type. DCX-copGFP HFBSCs became green-fluorescent after integration into the explants, confirming neuronal differentiation of the cells. These results show that HFBSC-derived neuronal progenitors are migratory and can integrate into cochlear modiolus explants, while adapting their phenotype depending on this micro-environment. Thus, HFBSCs show potential to be employed in cell-based therapies for auditory nerve repair

Nr4a1-eGFP Is a Marker of Striosome-Matrix Architecture, Development and Activity in the Extended Striatum

Transgenic mice expressing eGFP under population specific promoters are widely used in neuroscience to identify specific subsets of neurons in situ and as sensors of neuronal activity in vivo. Mice expressing eGFP from a bacterial artificial chromosome under the Nr4a1 promoter have high expression within the basal ganglia, particularly within the striosome compartments and striatal-like regions of the extended amygdala (bed nucleus of the stria terminalis, striatal fundus, central amygdaloid nucleus and intercalated cells). Grossly, eGFP expression is inverse to the matrix marker calbindin 28K and overlaps with mu-opioid receptor immunoreactivity in the striatum. This pattern of expression is similar to Drd1, but not Drd2, dopamine receptor driven eGFP expression in structures targeted by medium spiny neuron afferents. Striosomal expression is strong developmentally where Nr4a1-eGFP expression overlaps with Drd1, TrkB, tyrosine hydroxylase and phospho-ERK, but not phospho-CREB, immunoreactivity in “dopamine islands”. Exposure of adolescent mice to methylphenidate resulted in an increase in eGFP in both compartments in the dorsolateral striatum but eGFP expression remained brighter in the striosomes. To address the role of activity in Nr4a1-eGFP expression, primary striatal cultures were prepared from neonatal mice and treated with forskolin, BDNF, SKF-83822 or high extracellular potassium and eGFP was measured fluorometrically in lysates. eGFP was induced in both neurons and contaminating glia in response to forskolin but SKF-83822, brain derived neurotrophic factor and depolarization increased eGFP in neuronal-like cells selectively. High levels of eGFP were primarily associated with Drd1+ neurons in vitro detected by immunofluorescence; however ∼15% of the brightly expressing cells contained punctate met-enkephalin immunoreactivity. The Nr4a1-GFP mouse strain will be a useful model for examining the connectivity, physiology, activity and development of the striosome system

Integrins promote axonal regeneration after injury of the nervous system.

Integrins are cell surface receptors that form the link between extracellular matrix molecules of the cell environment and internal cell signalling and the cytoskeleton. They are involved in several processes, e.g. adhesion and migration during development and repair. This review focuses on the role of integrins in axonal regeneration. Integrins participate in spontaneous axonal regeneration in the peripheral nervous system through binding to various ligands that either inhibit or enhance their activation and signalling. Integrin biology is more complex in the central nervous system. Integrins receptors are transported into growing axons during development, but selective polarised transport of integrins limits the regenerative response in adult neurons. Manipulation of integrins and related molecules to control their activation state and localisation within axons is a promising route towards stimulating effective regeneration in the central nervous system

Asset pricing models, anomalies and extra-financial criteria

Les prix des actifs financiers reflètent-ils toutes les informations antérieures ainsi que toutes celles qui sont publiques ? La théorie de l’efficience informationnelle, dans une forme semi-forte (Fama, 1970), stipule que les prix des titres représentent, à tout moment, leurs valeurs intrinsèques respectives. Tester cette théorie impose de recourir à un modèle de formation des prix, le MÉDAF. Seulement, ce modèle, dans un contexte empirique, n'explique pas des portions significatives des rentabilités : les anomalies. Que conclure ? S’agit-il d’un modèle mal spécifié ou bien d’un modèle valide qui, dans ses échecs, indique que les marchés sont inefficients ? Fama et French (1992) avancent que le risque d’un actif est une combinaison de plusieurs facteurs de risque. Les anomalies de marché, selon ces auteurs, n’existent pas. Elles résultent de l’omission de facteurs de risque qui influencent la formation du prix que le seul beta du marché ne capture pas. Les auteurs formalisent un modèle à trois (1993) puis à cinq facteurs empiriques (2015) afin d’expliquer l'intégralité des rentabilités ex post en séries chronologiques ainsi qu'en coupe transversale. C’est dans cette démarche que ce travail de thèse s’inscrit. Malgré leurs carences en fondements théoriques, les modèles ad-hoc peuvent-ils gagner une forme de légitimité en intégrant un contenu informationnel large et en apparaissant comme des solutions pertinentes et efficaces pour l'estimation du risque des actifs financiers. À partir d'un échantillon français de 1 163 titres sur la période 1990-2016 et d'un échantillon européen de 12 144 actions entre 2002 à 2015, trois études empiriques sont produites. La première interroge le caractère généralisable des modèles multifactoriels à l'échelle nationale et plus précisément à destination du marché hexagonal. La seconde étude cherche à s'affranchir des limites du MÉDAF en ajoutant les co-moments d'ordres trois et quatre dans les combinaisons de facteurs testés. Dans un axe de généralisation du MÉDAF, le caractère asymétrique (co-skewness) et leptokurtique (co-kurtosis) des distributions de rentabilité constitue-t-il un apport informationnel susceptible d'expliquer les anomalies de marché rendant, par voie de conséquence, les primes de risque caduques ? Dans un troisième essai portant sur le marché européen, nous testons l'hypothèse selon laquelle la notation extra-financière constitue une information publique intégrée dans les cours. Dans ce contexte régional, quid de la capacité des modèles multifactoriels à intégrer une dimension du risque associé à la notation extra-financière. Nous montrons que la notation extra-financière portant sur les dimensions environnementales, sociales et de gouvernance (ESG) approxime un contenu informationnel perçu par les investisseurs comme un facteur de risque. En cela, les modèles ad-hoc montrent une capacité explicative supérieure à celle du modèle de marché. Ils permettent d'intégrer des contenus informationnels larges et disparates non captés par le beta et trouvent en cela une forme de légitimité dans l'estimation du risque des actifs financiers.Do the prices of financial assets reflect all previous information as well as all that is public? The efficient market hypothesis (EMH), in a semi-strong form (Fama, 1970), states that securities prices represent, at all times, their respective intrinsic values. Testing this EMH requires the use of an asset pricing model, the CAPM. However, it does not explain significant portions of the returns: the market anomalies. What to conclude? Is it a misspecified model or a valid one that, in its failures, indicates that markets are inefficient? Fama and French (1992) argue that the risk of an asset is a combination of several risk factors. Market anomalies, according to these authors, do not exist. They result from the omission of risk factors that influence the formation of the price that the beta of the market does not capture. The authors formalize a three (1993) and a five factor model (2015) to explain the completeness of the ex post returns in time series as well as in cross section. Despite their shortcomings in theoretical foundations, can ad-hoc models gain some form of legitimacy by integrating broad informational content and appearing as relevant and effective solutions for risk estimation of financial assets. From a French sample of 1,163 individual securities over the period 1990-2016 and from a European one of 12,144 stocks between 2002 and 2015, three empirical studies are done. The first interrogates the generalizability of multifactorial models at the national level and more specifically to the French market. The second study seeks to overcome the limitations of the CAPM by adding co-moments of orders three and four in the combinations of factors tested. In an axis of generalization of the CAPM, do the co-skewness and the co-kurtosis constitute an informational contribution likely to explain the market anomalies, which consequently makes the risk premiums outdated? In a third essay on the European market, we test the EMH through the extra-financial rating. This rating is a public information integrated into the prices. In this regional context, what about the ability of multifactor models to integrate a dimension of the risk associated with the extra-financial rating? We show that this rating of environmental, social and governance (ESG) dimensions approximates information content perceived by investors as a risk factor. Ad-hoc models show a higher explanatory power than the ex post CAPM. They succeed in integrating broad and disparate information contents not captured by the beta and find in this, a form of legitimacy for estimating the risk of financial assets

Modèles d'évaluation des actifs financiers, anomalies et notation extra-financière

Do the prices of financial assets reflect all previous information as well as all that is public? The efficient market hypothesis (EMH), in a semi-strong form (Fama, 1970), states that securities prices represent, at all times, their respective intrinsic values. Testing this EMH requires the use of an asset pricing model, the CAPM. However, it does not explain significant portions of the returns: the market anomalies. What to conclude? Is it a misspecified model or a valid one that, in its failures, indicates that markets are inefficient? Fama and French (1992) argue that the risk of an asset is a combination of several risk factors. Market anomalies, according to these authors, do not exist. They result from the omission of risk factors that influence the formation of the price that the beta of the market does not capture. The authors formalize a three (1993) and a five factor model (2015) to explain the completeness of the ex post returns in time series as well as in cross section. Despite their shortcomings in theoretical foundations, can ad-hoc models gain some form of legitimacy by integrating broad informational content and appearing as relevant and effective solutions for risk estimation of financial assets. From a French sample of 1,163 individual securities over the period 1990-2016 and from a European one of 12,144 stocks between 2002 and 2015, three empirical studies are done. The first interrogates the generalizability of multifactorial models at the national level and more specifically to the French market. The second study seeks to overcome the limitations of the CAPM by adding co-moments of orders three and four in the combinations of factors tested. In an axis of generalization of the CAPM, do the co-skewness and the co-kurtosis constitute an informational contribution likely to explain the market anomalies, which consequently makes the risk premiums outdated? In a third essay on the European market, we test the EMH through the extra-financial rating. This rating is a public information integrated into the prices. In this regional context, what about the ability of multifactor models to integrate a dimension of the risk associated with the extra-financial rating? We show that this rating of environmental, social and governance (ESG) dimensions approximates information content perceived by investors as a risk factor. Ad-hoc models show a higher explanatory power than the ex post CAPM. They succeed in integrating broad and disparate information contents not captured by the beta and find in this, a form of legitimacy for estimating the risk of financial assets.Les prix des actifs financiers reflètent-ils toutes les informations antérieures ainsi que toutes celles qui sont publiques ? La théorie de l’efficience informationnelle, dans une forme semi-forte (Fama, 1970), stipule que les prix des titres représentent, à tout moment, leurs valeurs intrinsèques respectives. Tester cette théorie impose de recourir à un modèle de formation des prix, le MÉDAF. Seulement, ce modèle, dans un contexte empirique, n'explique pas des portions significatives des rentabilités : les anomalies. Que conclure ? S’agit-il d’un modèle mal spécifié ou bien d’un modèle valide qui, dans ses échecs, indique que les marchés sont inefficients ? Fama et French (1992) avancent que le risque d’un actif est une combinaison de plusieurs facteurs de risque. Les anomalies de marché, selon ces auteurs, n’existent pas. Elles résultent de l’omission de facteurs de risque qui influencent la formation du prix que le seul beta du marché ne capture pas. Les auteurs formalisent un modèle à trois (1993) puis à cinq facteurs empiriques (2015) afin d’expliquer l'intégralité des rentabilités ex post en séries chronologiques ainsi qu'en coupe transversale. C’est dans cette démarche que ce travail de thèse s’inscrit. Malgré leurs carences en fondements théoriques, les modèles ad-hoc peuvent-ils gagner une forme de légitimité en intégrant un contenu informationnel large et en apparaissant comme des solutions pertinentes et efficaces pour l'estimation du risque des actifs financiers. À partir d'un échantillon français de 1 163 titres sur la période 1990-2016 et d'un échantillon européen de 12 144 actions entre 2002 à 2015, trois études empiriques sont produites. La première interroge le caractère généralisable des modèles multifactoriels à l'échelle nationale et plus précisément à destination du marché hexagonal. La seconde étude cherche à s'affranchir des limites du MÉDAF en ajoutant les co-moments d'ordres trois et quatre dans les combinaisons de facteurs testés. Dans un axe de généralisation du MÉDAF, le caractère asymétrique (co-skewness) et leptokurtique (co-kurtosis) des distributions de rentabilité constitue-t-il un apport informationnel susceptible d'expliquer les anomalies de marché rendant, par voie de conséquence, les primes de risque caduques ? Dans un troisième essai portant sur le marché européen, nous testons l'hypothèse selon laquelle la notation extra-financière constitue une information publique intégrée dans les cours. Dans ce contexte régional, quid de la capacité des modèles multifactoriels à intégrer une dimension du risque associé à la notation extra-financière. Nous montrons que la notation extra-financière portant sur les dimensions environnementales, sociales et de gouvernance (ESG) approxime un contenu informationnel perçu par les investisseurs comme un facteur de risque. En cela, les modèles ad-hoc montrent une capacité explicative supérieure à celle du modèle de marché. Ils permettent d'intégrer des contenus informationnels larges et disparates non captés par le beta et trouvent en cela une forme de légitimité dans l'estimation du risque des actifs financiers