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The Functional Roles of Plexind1 in Chicken Nervous System During Development

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The Functional Roles of Plexind1 in Chicken Nervous System During Development Research Collection Doctoral Thesis The functional roles of PlexinD1 in chicken nervous system during development Author(s): Gemayel, Joëlle Publication Date: 2005 Permanent Link: https://doi.org/10.3929/ethz-a-005004364 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH No. 15930 The functional roles of PlexinD1 in chicken nervous system during development A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZURICH for the degree of Doctor of Sciences presented by JOËLLE GEMAYEL DEA “Metabolism, Endocrinologie et Nutrition” Université Claude Bernard-Lyon born May 27, 1974 citizen of Lebanon accepted on the recommendation of Prof. Martin Schwab, examiner Prof. Lukas Sommer, co-examiner Dr. Matthias Gesemann, external supervisor 2005 DISS. ETH No. 15930 The functional roles of PlexinD1 in chicken nervous system during development A dissertation submitted to the SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZURICH for the degree of Doctor of Sciences presented by JOËLLE GEMAYEL DEA “Metabolism, Endocrinologie et Nutrition” Université Claude Bernard-Lyon born May 27, 1974 citizen of Lebanon accepted on the recommendation of Prof. Martin Schwab, examiner Prof. Lukas Sommer, co-examiner Dr. Matthias Gesemann, external supervisor 2005 Summary A functional nervous system results from the coordinated generation and assembly of billions of neural cells into highly structured and well organized networks. Building blocks for these networks are neurons, which arise from neural progenitors that are deployed from specialized neuroepithelia. These neuronal precursors migrate along specific pathways populating different areas within the developing brain, spinal cord and peripheral nervous system. Once correctly positioned, differentiated neurons send out axons along highly stereotypical pathways, specifically linking neurons within different parts of the nervous system, generating a high number of functional neuronal networks. The use of appropriate migratory routes as well as directed axonal outgrowth along specific predetermined pathways is achieved by specific receptor-ligand interactions that are characteristic for each subpopulation of migratory cells or growing axons. Several families of cell surface receptors and axon guidance cues involved in directing cell migration and/or axonal outgrowth have been described over the last decade. One of the largest families of axon guidance receptors is the plexin family. Plexins and their semaphorin ligands have been shown to be involved in several aspects of axonal targeting and cell migration. However, numerous studies describe also functional roles for plexins in the development outside the nervous system, notably in the development of the cardiovascular system. In this respect, PlexinD1 (PD1) has been extensively studied in vasculogenesis, and several groups document its implication in heart development as well as in vessel patterning. However, PD1 is also expressed in several regions of the developing brain, but no available data describe its potential role in the nervous system. Experiments in the first part of this thesis demonstrate that PD1 transcripts are not only found in mouse brain but also in chicken spinal motor neurons during the period motor axons sort in the limb plexus. PD1 knock down, using in ovo RNAi, results in motor axon misguidance in the dorsal as well as the ventral crural nerve trunk, suggesting PD1 involvement in motor axon guidance and/or sorting of the crural nerve. Interestingly, PD1 loss of function experiments showed also unexpected defects in dorsal sensory root formation and abnormalities in the area of motoneuron exit points. In PD1 knock down animals, dorsal roots are less compact, and several axon bundles grow erroneously into neighboring segments whereas motor exit points display a severely altered morphology appearing much broader than usual, and the ventral motor roots show axons with aberrant courses. i ii Summary While the defects in the crural nerve could be easily explained by the lack of PD1 expression in motoneurons, phenotypes observed in the dorsal and ventral roots support a role for PD1 in either neural crest migration or the existence of a tight relation between intersomitic vessel formation and dorsal root development. In the first case, PD1 loss of function in a subpopulation of neural crest cells would lead to erroneous positioning of Schwann cells and /or boundary cap cells resulting in outgrowth and defasciculation defects within the ventral and dorsal roots. Alternatively, PD1 knock down might affect endothelial cells surrounding the spinal cord, in particular the intersomitic vessels, leading to aberrant formation of these vessels. Intersomitic vessels could form in close contact with sensory growing axons and could play a role for correct axonal outgrowth. Their aberrant formation could result, therefore, in axon guidance defects observed in the present study. Experiments described in the second and third chapter of this thesis analyze the presence and expression of semaphorins as well as plexins in the developing chicken spinal cord. Chicken plexins and semaphorins display very complex, often complementary, but also overlapping expression patterns that are highly regulated developmentally. These results suggest multifunctional roles for these proteins, most likely exerting their activities in large complexes containing intricate combinations of several members. Résumé Le bon fonctionnement du système nerveux dépend du correct assemblage de milliards de cellules neurales générées pendant le développement embryonnaire afin de pouvoir former des réseaux complexes et structurés. Les précurseurs des cellules neurales se forment au niveau d’une structure bien spécialisée appelée l’épithélium neuronal. Une fois générées, ces cellules entament leur migration tout le long de parcours bien définis afin de former les différentes structures du système nerveux central et périphérique. Par la suite les cellules neuronales projettent leurs axones tout le long de voies bien définies, souvent à de très longues distances de leur corps cellulaire pour finalement de se connecter à leur cible finale. L’achèvement d’une migration cellulaire correcte ainsi que la navigation précise des axones jusqu’à leur destination finale dans un système embryonnaire nécessite l’intégrité de familles de protéines parmi lesquelles les plexines. Les plexines ont été récemment identifiées et caractérisées; elles constituent une très grande famille de protéines contenant environ 9 membres et exercent leur action en se liant à leur ligands, les semaphorines. Plusieurs études décrivent l’implication de ces protéines dans le développement du système nerveux central mais aussi dans la formation d’autre tissues embryonnaires. PlexinD1 appartient à la famille des plexines et a été intensivement décrite comme un facteur majeur dans le développement du système vasculaire in vitro et in vivo. Bien que l’expression de cette protéine ait été identifiée dans le cerveau de souris pendant le développement embryonnaire, aucune étude ne décrit le rôle de plexinD1 dans le développement du système nerveux central. Pendant ce travail de thèse, nous avons souhaité investir le rôle potentiel de plexinD1 dans le développement de la moelle épinière dans l’embryon de poulet. Nous avons établi que cette protéine est bien exprimée pendant le développement par les neurones moteurs de la moelle épinière et cette expression correspond au moment où ces neurones s’arrangent dans le plexus à la base du pied. Les outils moléculaires visant à bloquer l’expression de plexinD1 en utilisant une technique appelée in ovo RNAi, ont pu démontrer que l’absence de plexinD1 dans les motoneurones induit la malformation de certaines branches du nerf crural. De plus, nous avons observé des anomalies au sein des fibres sensorielles résultant en la fusion des fibres entre elles, bien que plexinD1 ne soit pas exprimée par les neurones sensorielles mais par les cellules endothéliales iii iv Résumé entourant la moelle épinière et les ganglions de la racine dorsale. Afin de pouvoir expliquer ces aberrations dans la formation des fibres sensorielles, nous avons proposé deux modèles. Notre première hypothèse suppose que plexinD1 n’est pas exclusivement exprimée par les cellules endothéliales mais aussi dans les cellules de Schwann et les boundary cap cells. Une migration erronée de ces cellules menant à leur mauvais positionnement peut expliquer les anomalies observées. Une seconde explication est que la malformation des fibres sensorielles peut résulter d’une anomalie dans le développement des vaisseaux sanguins exprimant plexinD1, en particulier les vaisseaux intersomitiques, qui normalement assistent et guident les fibres sensorielles pendant leur élongation. Nous avons également montré dans une deuxième partie de notre travail, l’expression de toutes les semaphorines et plexines dans la moelle épinière du poulet au cours des différents stades du développement. Nos résultats démontrent que les ARNm étudiés sont exprimés d’une façon très complexe et dynamique suggérant l’existence de multiples fonctions exercées par ces protéines qui très souvent doivent agir en synergie plutôt que séparément. Acknowledgements I would like to thank Dr. Matthias Gesemann for giving me the opportunity to do my PhD thesis in his laboratory and introducing
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