From inside-out to outside-in: cortical lamination development in the Reelin-deficient neocortex
von Nieves Mingo Moreno
Datum der mündl. Prüfung:2018-03-23
Erschienen:2019-03-15
Betreuer:Prof. Dr. Jochen F. Staiger
Gutachter:Prof. Dr. Thomas Dresbach
Gutachter:Prof. Dr. Ahmed Mansouri
Zum Verlinken/Zitieren:
http://dx.doi.org/10.53846/goediss-7335
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Name:Thesis_Nieves_Mingo_Moreno_(eDISSfinal).pdf
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Zusammenfassung
Englisch
The adult mammalian neocortex is divided into six vertical layers, as well as into numerous specialized tangential areas that are defined by distinct cytoarchitectures and specific wiring patterns. Precise neocortical function depends on the accurate development of these layers and areas. The formation of layers relies, on an appropriate cell production, migration and positioning during embryonic and early postnatal stages. The large extracellular matrix glycoprotein Reelin, encoded by the reelin (Reln) gene (D'Arcangelo et al., 1999) and secreted by Cajal-Reztius cells in the marginal zone of the developing neocortex, plays a key role in orchestrating these events. The reeler mouse strain (Falconer, 1951), a mouse with a homozygous loss of function of the reelin gene, played a fundamental role in the process of understanding normal brain development and directed the hypothesis about Reelin function. However, diverse models of Reelin action, influenced by the incomplete description of the reeler phenotype, have been proposed and still remain controversial. On the basis of layer-specific mRNA expression we could demonstrate that the reeler cortex, usually described as “inverted”, is disrupted in a more complex and, highly area dependent manner. These cortical lamination patterns range from an intermingled, but more similar to the wild type phenotype in the rostral motor cortex (quasi-wild type), via an almost layer- disappearance in the intermediate somatosensory cortex, to a more inverted phenotype in the caudal visual cortex (quasi-inverted). Developmentally, the distribution of early- and late- born neurons (establishing infra- vs. supragranular layers in wild type) are largely non-consistent across cortical regions in reeler. These differences create an inside-out to an outside-in lamination gradient, through the anterior-posterior axis in of the reeler cortex. In line with these data, the expression of preplate-specific genes and trajectories of thalamic fibers during development, indicate that preplate splitting is altered, but generally takes place in rostral cortical areas, while it is completely absent in the caudal cortex. Neocortical neurogenesis and neuronal migration was examined in Reelin-deficient mice, making use of in utero electroporation, FlashTag labeling and a novel nucleoside analog cell birth-dating techniques. We could demonstrate that in the absence for Reelin, neurogenesis seems to be unaffected and that direct as well as indirect VZ- and SVZ born progeny contribute to the cellular intermingling. We also could show that, at early stages of migration, cells migrate as a cohesive population, and neuronal morphology, cell polarity and radial migration is preserved in the rostral motor cortex as well as the caudal visual cortex in reeler. However, the various reeler phenotypes become apparent at the moment in which neurons enter the cortical plate. Despite an equivalent cell scattering, only late-born neurons in the rostral cortex are able to reach upper cortical levels and direct, at least partially, their dendrites upwards. In contrast, late-born neurons in the caudal cortex ectopically stop migrating and differentiate closer to the white matter, extending its processes towards various and unpredictable directions. The data from the present study demonstrate that the neocortex should not be considered generally and highlights the complexity of the Reelin-deficient neocortex. Our results also indicate that cell-type an area-dependent secondary effects due to the absence of Reelin should be taken into account for the evaluation of the reeler neocortex.
Keywords: Neocortex; Neuronal migration; Cortical lamination; reeler
