SYNERGY OF REELIN SOURCES IN CORTICAL LAMINATION

Reelin (Reln) is a large glycoprotein regulating multiple stages of mammalian cortical development, including neuronal migration, dendrite formation and neuronal plasticity. In both humans and rodents, homozygous mutations are associated with severe neuronal migration disorders, while heterozygous mutations or reduced levels are reported in most neurodevelopmental disorders (NDDs) and associated with deficits in neuronal cytoarchitecture and plasticity. Importantly, during development, Reln is secreted by sequential cellular sources from distinct origins and molecular profiles. At the onset of cortical neurogenesis, 4 populations of Cajal-Retzius cells (CRs) are generated by focal domains of progenitors and represent the main source of Reln during embryonic stages, before undergoing massive apoptosis during the first postnatal weeks. From mid-neurogenesis, several subpopulations of cortical GABAergic interneurons (INs) start secreting Reln and eventually become the main Reln source in the adult neocortex. However, the specific functions of Reln sources in cortical development remains poorly addressed.
We generated genetic models to conditionally ablate reln either ubiquitously with different efficacy, or specifically in subpopulations of CRs and/or INs. At first, using early CAG-CRE-ER induction, we identify layer-specific sensitivities to Reln levels. Furthermore, using CRs and INs- CRE lines, we describe specific and cooperative roles for Reln sources in cortical lamination, and characterize their local contributions along cortical areas. Finally, we reveal inter-sources compensatory mechanisms to maintain Reln cortical levels, and explore their cellular and molecular origins. Together, these results provide critical insights into the role of Reln deficits in cortical development and its implication across the phenotypic diversity of NDDs.