Reelin et développement cérébral : état de la question depuis le clonage du gène

Abstract

Reelin est la proteine produite par le gene mute chez les souris reeler. Reeler est une mutation recessive autosomique, initialement decrite voici 50 ans. Elle provoque des anomalies de l' organisation cytoarchitectonique de nombreuses regions cerebrales, parmi lesquelles le neocortex, l' hippocampe et le cervelet. Ces anomalies, qui touchent specifiquement la phase terminale de la mise en place des neurones au cours du developpement, sont utilisees depuis longtemps comme modele d' etude du developpement cerebral. La Reelin, produite par certains neurones du systeme nerveux central comme les cellules de Cajal-Retzius, agit localement, de maniere paracrine ou "juxtacrine", sur d' autres cellules cibles, par exemple les cellules de la plaque corticale. Ces dernieres, lorsqu' elles sont mises en presence de Reelin, reagiraient en activant une cascade de phosphorylations, ce qui leur permettrait de s' ordonner correctement pour former le modele architectonique radiaire typique de la plaque corticale precurseur du cortex normal.

Reelin is the protein defective in reeler mice, which are characterized by abnormal architectonic development. Reelin is an extracellular matrix protein specific of the embryonic brain and produced by Cajal-Retzius cells and a few other cell types. The reelin gene is about 400-450 kbp-long and composed of 65 exons; it contains a repeated structure thought to result from gene duplication. Two alternative forms of the reelin mRNA are found, namely facultative inclusion of a 6 nt microexon or alternative polyadenylation, the function of which is unknown. Monoclonal antibodies have been produced against both extremities of the protein and allow the study of native Reelin in embryonic brain extracts. Using these antibodies, the Orleans allele of reeler was shown to result from defective secretion of a truncated Reelin. When Reelin distribution was studied during development using both immunohistochemistry and in situ hybridization, no correlation was found between expression and the reeler phenotype, suggesting that Reelin acts in a juxtacrine fashion in the extracellular matrix, on adjacent target cells. The presence of reelin mRNA was demonstrated in the embryonic brain of birds and reptiles, a finding compatible with the hypothesis that Reelin played a role in cortical evolution. Recent work showed that mice deficient in the disabled1 (Dab1) kinase adaptor have a reeler phenotype but express normal amounts of Reelin, and that scrambler/yotari, two mutants with a reeler phenotype, are mutations of Dab1. Furthermore, mice deficient in the kinase Cdk5 and, to a lesser extent, in its cofactor p35, also have reeler-like brain anomalies. These findings strongly implicate a kinase cascade in the transduction of the signal initiated by reelin at the level of target neurons. [References: 29]