La corticogenèse et la gliogenèse cérébrales : influence de facteurs d'environnement
(1995)
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Details
- Authors
- Supervisors
- Evrard, Philippe
- Abstract
- Over the last two decades, advances in developmental neurobiology, especially with regard to mechanisms of neuronal migration, of angiogenesis and of gliogenesis, have revolutionized our understanding of the environmental determinants of nervous system development. <BR> The purpose of the present work is to investigate the functions of glial population during mammalian cortical development and to characterize the disturbances of gliogenesis and neurogenesis induced by several environmental factors. In order to approach these questions, we studied the ontogenesis and organization of the successive glial neocortical populations in normal conditions and under the influence of selected environmental factors. The deleterious consequences of glial disturbances on cortical architectony are analyzed and discussed. <BR> Two basic questions of developmental neurobiology refer to the origin and production of neural cell lineages and to the mechanisms controlling the organized distribution of cortical neurons at distance from their site of production. As soon as the neural tube is closed, a glial phenotype appears in the primitive neuroepithelium. These glial cells are rapidly organized in fascicules, before the onset of neuronal migration. The fascicular organization of the glial fibers which are used as guides I migrating neurons is maintained throughout mammalian evolution. The conservation of this ontogenic unit made of the glial fascicule and its affiliated migrating neurons suggests that this neuronal-glial unit could represent a phylogenic entity; the increase of brain size through mammalian evolution could be partly due to an increased number of these adjacent neuronal-glial modules. While white matter astrocytes are derived from the transformation of the radial glial fibers, the late germinative zone produces, after the end of neuronal migration, glial cells which migrate and give rise to astrocytes in the upper cortical plate. The inhibition by an antimitotic drug of this late astroglial production induces a dramatic neuronal death in the upper cortex. These results demonstrate a dual origin of cortical astrocytes and indicate the critical role of astrocytes for a normal cortical function and organization. Furthermore, this animal provides a new hypothesis which could explain some neuropsychological abnormalities observed in premature infants affected by periventricular haemorrhages with partial destruction of the late germinative zone or by periventricular leucomalacias forming screens interrupting the migratory corridors for the late astrocytes. <BR> In order to develop a tool allowing to perform a fin teratology, mouse postimplantation embryos are cultured in toto at an early developmental stage in the presence of several environmental factors. At this embryonic stage, the neural tube is characterized by an intense mitotic activity as well as by the early appearance of a glial phenotype. In this model, low doses of cocaine inhibit the glial maturation. These data are confirmed and extended by the demonstration of an in vivo reduction of the density of radial glial fibers in embryos treated with cocaine. Furthermore, these treated embryos displays severe abnormalities of cortical architecting which could be the consequences of the decreased amount of glial guides. These cortical dysgeneses could represent the neuropathological substrate of neuropsychological perturbations affecting many infants born from mother addicted to cocaine. Finally, a molecular mechanism of the teratological action of cocaine is described: cocaine induces the expression of several immediate early genes such as c-fos and c-jun. <BR> Although the early gliogenesis is not affected by ethanol on the embryo culture model, ethanol induces an early transformation of radial glial cells into astrocytes destined to the white matter before completion of neuronal migrations as well as a delayed production of the astrocytic equipment of the upper cortex in the late germinative zone. These alterations of cortical gliogenesis provide clues to understand the frequent cortical dysgenese observed in human fetal alcohol syndromes. These cortical abnormalities include white matter and subpial neuronal ectopias and a disturbed laminar organization of cortical neurons. <BR> Although VIP is produced by adult brain and its receptor is abundantly distributed in embryonic brain, the mARN coding for VIP is not detected in the developing nervous system before birth in rodents. The detection of circulating VIP in maternal blood and the ability of VIP to cross the placenta conduct us to propose that VIP acts on developing brain tissues as an extra-embryonic factors. This original concept provides a new way to study the developmental relation between the mother and its embryo. The embryo culture technique shows that VIP is a critical endocrine factor regulating the growth effects of VIP are controlled by several mechanisms displaying a tissular specificity and implying at least two pharmacologically distinct receptors. These data open new avenues of interactions between embryology and developmental neurobiology. Furthermore, this study underlines the complexity of the mechanisms regulating the number of precursors cells which will give rise to the whole brain. The in vivo inhibition of the mitogenic activity of VIP by a specific VIP antagonist for a critical 72 hour period (between the closure of neural tube and the onset of neuronal migration) produces a 50% microcephaly without any possibility of subsequent growth catch up. These data offer a new molecular mechanism which could explain some human microcephalies and demonstrate the crucial role of this early embryonic period for the future of the developing brain. <BR> The design and use of animal models as well as the combination of original conceptual and methodological tools reveal some critical aspects of normal gliogenesis. Several molecular and/or cellular alterations of the successive steps of cortical gliogenesis appear as potential mechanisms of developing brain malformations induced by extra-embryonic factors. Furthermore, the crucial role played by the primitive neuroepithelium in determining the final brain volume is demonstrated. The etiology and the pathophysiological mechanisms of microcephalies are discussed. These malformations of murine neocortex represent models of frequent human pathological conditions such as alcohol and cocaine fetal syndromes, periventricular hemorrhages and leucomalacias of the premature infant and microcephalies of unknown etiology. In the future, these experimental tools should unravel some molecular and cellular mechanisms regulating the successive steps of gliogenesis in normal conditions and under the influence of environmental factors. <BR> In conclusion, the aim of the present work was to bring together the fields of developmental neurobiology, embryology, teratology and environment sciences. These experiments permitted to demonstrate that, during the developmental steps corresponding to the two first trimesters of human pregnancy, environmental factors disrupt the neocortical architectonics through disturbing the glial guidance of neuronal migrations (which determines the location of neuronal functioning) as well as the chronology and intensity of the mitotic activity of neuronal and astroglial precursors.
- Affiliations
Citations
Gressens, P. (1995). La corticogenèse et la gliogenèse cérébrales : influence de facteurs d’environnement. https://hdl.handle.net/2078.5/124438