Reelin protein and a secret of human brain development

The correct development of the cerebral cortex is an essential process for the acquisition of adequate cognitive abilities. Reelin, a key extracellular protein in neuronal migration and synaptic plasticity, is decisive in this process. For this reason, the dysfunction (either genetic or at the expression level) of this extracellular protein is implicated in neurodevelopmental pathologies —such as lissencephaly, epilepsy or some psychiatric diseases, especially autism, schizophrenia and bipolar disorder— or also neurodegenerative diseases.

Now, a study reveals the decisive role of reelin expressed by Cajal-Retzius (CR) pioneer neurons or cortical GABAergic interneurons in the process of corticogenesis and neuronal migration. The study has been directed by Professor Eduardo Soriano, from the Department of Cell Biology, Physiology and Immunology of the Faculty of Biology and the Institute of Neurosciences (UBNeuro) of the University of Barcelona (UB), and the Center for Biomedical Research in Network on Neurodegenerative Diseases (CIBERNED), in Spain, and its first authors are the researchers Alba Vílchez and Yasmina Manso (UB-UBNeuro-CIBERNED).

The work is based on the study of genetically modified mice to selectively inactivate the reelin gene in pioneer CR neurons and cortical GABAergic interneurons. While CR cells play a key role in early stages, “the study highlights the fundamental role of reelin derived from GABAergic interneurons in late neuronal migration,” says Professor Eduardo Soriano.

Reelin deficiency in Cajal-Retzius cells during development alters the migration of neurons destined for higher layers (green) that remain ectopically located in lower layers of the cerebral cortex. These images have been captured by confocal microscopy and then processed. (Images: UB)

A new model of action of the reelin protein

The team has also described the existence of transient migratory deficits in some neuronal populations, a process that indicates that the reelin expressed by any of the neuronal populations is sufficient to reverse and compensate for some defects in cortical lamination in the brain. Based on the results of their study, the authors propose a new model of reelin action in the development of the cerebral cortex based on the cooperation and spatial, cellular and sequence-specific expression of this key protein.

Various neuropsychiatric disorders are linked to alterations in neuronal migration and reelin deficits in interneurons. “Thus, this study may provide a better understanding of the mechanisms associated with disorders in the human brain related to reelin deficits associated with migration disorders,” the research team concludes.

Also co-authors of the study are Marta Pascual and Alba Elías-Tersa (UB-UBNeuro-CIBERNED); Víctor Borrell and Adrián Cárdenas, from the Institute of Neurosciences (CSIC-Miguel Hernández University); Manuel Álvarez-Dolado and Magdalena Martínez-Losa, from the Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), and Angus C. Nairn, from Yale University (United States).

The study is entitled “Specific contribution of Reelin expressed by Cajal–Retzius cells or GABAergic interneurons to cortical lamination”. And it has been published in the academic journal Proceedings of the National Academy of Sciences (PNAS). (Source: UB)