| dc.description.abstracteng | 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. | de |