Role of the small GTPase RhoE in myelination and axonal tracts development

• Autores: María del Pilar Madrigal Verdú
• Directores de la Tesis: Ignacio Pérez Roger (dir. tes.), José Terrado Vicente (codir. tes.)
• Lectura: En la Universidad CEU - Cardenal Herrera ( España ) en 2019
• Idioma: inglés
• Tribunal Calificador de la Tesis: Francisco Bosch-Morell (presid.), Juan A. Moreno-Bravo (secret.), Enrique Lanuza Navarro (voc.), Eduardo de Puelles Martínez de la Torre (voc.), Enric Mocholí (voc.)
• Enlaces
  • Tesis en acceso abierto en: Repositorio Institucional CEU
• Resumen

  • The Rho family of small GTPases is a group of proteins with important roles in actin cytoskeleton organization. In the last years, mounting evidences suggest that these proteins have key roles in the development and function of the central nervous system (CNS). In particular, Rnd proteins are a subfamily of Rho GTPases characterized by their constitutive activity. Rnd3/RhoE is a member of this subfamily, whose specific functions during brain development are still not well defined. Thus, the main aim of the present work is determine its role during the development of CNS by studying the anatomical and morphological consequences present in a transgenic mouse lacking the RhoE expression (RhoEgt/gt).

    The RhoEgt/gt mice display severe alterations in the brain. On the one hand, RhoEgt/gt mice exhibit hypomyelination in the brain. The mutants show a decreased expression of several myelin proteins, reduction in the number of myelinated axons and those that are myelinated display thinner myelin sheaths. The analysis of the RhoE expression showed that it is expressed in oligodendrocyte precursor cells and also in mature oligodendrocytes in vivo and in vitro. In fact, in the mutant, the striatum and the corpus callosum, showed a reduction in the number of mature and total oligodendrocytes. These results together with the in vitro cultures studies suggested that in RhoEgt/gt. On the other hand, RhoE mutants the differentiation of the oligodendrocyte precursor cells is altered. Altogether indicates that RhoE is directly required for the differentiation of oligodendrocytes and in consequence for the correct myelination of the CNS. RhoEgt/gt mice show aberrant axonal projections in the forebrain. Specifically, the anterior branch of the anterior commissure growths from the anterior olfactory nucleus but is missprojecting ventrally without reach or cross the midline. Moreover, the thalamocortical projection is also altered, and only few axons enter the telencephalon. During the development of these axonal tracts, RhoE is expressed both in origin (anterior olfactory nucleus and thalamus) and in the surrounding regions that the axons have to cross to reach to their targets. Hence, these data suggest that RhoE is key for the CNS development by controlling the extension of these axonal systems and/or the establishment of the territories essential for their axon pathfinding.

    In summary, the results of this work highlight the relevance of RhoE in multiple and essential processes occurring during the development of the forebrain, in particular the myelination and pathfinding of some of the major axonal tract in this brain region.