Biology subjects

Bahi-Buisson, N.

Publications and source records attributed to Bahi-Buisson, N..

5 recordsLinked to original sources

bioRxiv2024

Differential contribution of P73+ Cajal-Retzius cells and Reelin to cortical morphogenesis

Cajal-Retzius cells (CRs) are a peculiar neuronal type within the developing mammalian cerebral cortex. One of their best documented feature is the robust secretion of Reln, a glycoprotein essential for the establishment of cortical layers through the control of radial migration of glutamatergic neurons. We previously identified Gmnc as a critical fate determinant for P73+ CRs subtypes from the hem, septum and thalamic eminence. In Gmnc-/- mutants, P73+ CRs are initially produced, cover the telencephalic vesicle but undergo massive apoptosis resulting in their complete depletion at mid-corticogenesis. Here we investigated the consequence of such a CRs depletion on dorsal cortex lamination and hippocampal morphogenesis. We found preplate splitting occurs normally in Gmnc-/- mutants but is followed by defective radial migration arrest in the dorsal cortex, altered cellular organization in the lateral cortex, aberrant hippocampal progenitor proliferation resulting in abnormal CA1 folding and lack of vasculature development in the hippocampal fissure. We then performed conditional Reln deletion in P73+ CRs to evaluate its relative contribution and found that only radial migration defects were recapitulated. We concluded that at mid-corticogenesis, CRs-derived Reln is required for radial migration arrest and additionally identified Reln-independent functions for CRs in the control of hippocampal progenitor proliferation and vessel remodelling.

neuroscience↗

bioRxiv2022

Capturing the pathomechanisms of different disease severities in a human cerebral organoid model of LIS1-lissencephaly

Lissencephaly is a malformation of cortical development (MCD) characterized by reduced to absent gyri and a disorganized cortex, leading to severe neurological consequences in affected individuals, including epilepsy, intellectual disability, and reduced life expectancy. Treatments are purely symptomatic, and patients often remain refractory to them. Heterozygous mutations in the LIS1 gene, encoding a regulator of the microtubule motor dynein, cause LIS1-lissencephaly. For unknown reasons, LIS1-lissencephaly patients show marked differences in disease severity despite each carrying a heterozygous LIS1 mutation. We leveraged forebrain-type organoids from patients diagnosed with mild, moderate, or severe LIS1-lissencephaly to investigate, in a cytoarchitecture and multi-omics approach, disease and severity grade associated phenotypes, mechanisms, and rescue approaches. We identified alterations of the cytoarchitecture, progenitor cell homeostasis, and neurogenesis often with a severity-dependent gradient. Identified disease-linked molecular mechanisms were microtubule destabilization, WNT-signaling, protein metabolism, and perturbed cadherin- and unfolded protein-binding. Some mechanisms exhibited a severity-dependent gradient or were specific to a severe grade. We present strategies to reverse phenotypic changes in LIS1-patient organoids and identify mTOR pathway inhibitors in in silico drug repurposing analysis as potential novel therapeutic strategy. By probing the top hit drug, the mTOR inhibitor everolimus, we could indeed rescue severity-dependent phenotypic changes in LIS1-patient organoids. This study demonstrates that organoid-based modeling is sensitive in recapitulating disease severity, which presents an important step in patient stratification, and allows the development of novel personalized rescue strategies with therapeutic potential.

neuroscience↗

bioRxiv2021

Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.

neuroscience↗

bioRxiv2020

Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

Primary microcephaly and megalencephaly are severe brain malformations defined by reduced and increased brain size, respectively. Whether these two pathologies arise from related alterations at the molecular level is unclear. Microcephaly has been largely associated with centrosomal defects, leading to cell death. Here, we investigated the consequences of WDR81 loss of function, which cause severe microcephaly in patients. We show that WDR81 regulates endosomal trafficking of EGFR, and that loss of function leads to reduced MAP kinase pathway activation. Mouse radial glial progenitor cells knocked-out for WDR81 display reduced proliferation rates, leading to reduced brain size. These proliferation defects are rescued in vivo by the expression of megalencephaly-causing mutated Cyclin D2. Our results identify the endosomal machinery as an important regulator of RG cell proliferation rates and brain growth. They demonstrate that microcephaly and megalencephaly can be due to opposite effects on the proliferation rate of radial glial progenitors.

neuroscience↗

bioRxiv2020

MINPP1 prevents intracellular accumulation of the cation chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol polyphosphate phosphatase 1 gene (MINPP1). Patients were found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We found that patient-derived and genome edited MINPP1-/- induced pluripotent stem cells (iPSCs) are not able to differentiate efficiently into neurons. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakiphosphate (IP6), detected in HEK293, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis.

genetics↗