iReelAx: Interspecies analysis of Reelin Functions in Circuit Wiring and Neurodevelopmental Disorders – iReelAx

Reelin (Reln) is an extracellular matrix protein that has been involved in multiple steps of brain development including neuronal migration, dendritic arborization and synaptogenesis. In humans, homozygous RELN mutations leading to a loss of function lead to lissencephaly and cerebellar hypoplasia. More recently, several homozygous and heterozygous RELN variants have been identified as risk factors for multiple neuropsychiatric disorders, including epilepsy, schizophrenia, bipolar disorders, Autism Spectrum Disorders and Alzheimer’s disease. Reln mouse mutants show on the other hand, amongst a large panel of phenotypes, a deficit in the formation of the six-layered neocortex, largely due to a defect in neuronal migration of pyramidal neurons. Extensive studies over the years revealed that such defect is due to an absence of RELN production by several cellular sources including: i) transient superficial Cajal-Retzius cells which are present in the marginal zone from the earliest steps of corticogenesis and subsequently eliminated and ii) subsets of interneurons, which start to express RELN at the end of embryogenesis. While the roles of RELN in migration have been well described, the complex phenotypes of full Reln mouse mutants have precluded an in-depth analysis of the functions of this secreted factor in axonal and synaptic organization in vivo. Recently, we have shown that RELN graded distribution in the optic tectum of zebrafish acts a chemoattractant cue and is crucially involved in setting up the parallel laminar organization of incoming axons in this brain structure. Based on our results in zebrafish, we propose to investigate a novel putative role of RELN in the development of axonal and dendritic structural organization in layer 1 of the mammalian neocortex. Using a comparative in vitro and in vivo approach, we will then explore the activity of RELN on synaptic function and stabilization in mouse cortical layer 1 afferent fibers and in the zebrafish tectum innervating axons. In particular, cell type specific mutants in mouse and cell transplants in fish respectively, will enable us to fully decipher the various roles of RELN in circuit assembly. In a second step, because mutations in the RELN locus have been associated with a number of neurological disorders in human patients, we will explore the molecular mechanisms of RELN signaling in the development of these pathological conditions. To this end, we have further isolated novel and still unpublished mutations in the RELN locus that are associated with a wide range of neuropsychiatric and neurodevelopmental disorders and we will study the functional significance of this mutations in a number of in vitro and in vivo systems. Our preliminary analyses support the hypothesis that the spectrum of RELN related disorders might reflect the degree of the severity of RELN mutations. To directly test this possibility, we will use a complementary combination of animal models (mouse and zebrafish), ex vivo experiments and biochemical assays. Overall our study aims to decipher the functional role of RELN in cortical synaptic organization as well to understand its involvement in disease development with an aim to provide novel targets for more effective pharmacological treatments.