Biology subjects

Rancourt, D.

Publications and source records attributed to Rancourt, D..

3 recordsLinked to original sources

bioRxiv2026

SCN1A haploinsufficiency disrupts neural progenitor networks and accelerates neurogenesis in human Dravet syndrome forebrain assembloids

Dravet syndrome is a severe childhood neurological disorder caused mostly due to mutations in the sodium channel gene SCN1A. Although the disorder is widely attributed to dysfunction of inhibitory neurons, growing evidence suggests that disease mechanisms may begin much earlier during brain development. To investigate the developmental consequences of SCN1A haploinsufficiency, we generated patient-derived dorsal-ventral forebrain assembloids that model key features of human corticogenesis. We found that SCN1A was expressed in ventricular zone neural progenitors and that its reduced expression was associated with impaired growth, disrupted ventricular zone organization, and progressive depletion of progenitor populations. We further demonstrated reduced progenitor proliferation and self-renewal, accelerated cell-cycle exit, and premature neuronal differentiation, leading to increased production of excitatory neurons and enhanced network excitability. Single cell transcriptomic analyses revealed reduced cycling radial glial cells, accelerated progenitor maturation, and dysregulation of gap junction and calcium signaling pathways. Following these findings, we examined progenitor calcium activity and found that SCN1A haploinsufficiency disrupted coordinated functional network organization, resulting in reduced recurrent connectivity and fragmentation of functional cellular assemblies. These abnormalities occurred despite preserved intrinsic electrophysiological properties of individual progenitors, indicating a defect in population-level coordination rather than single cell electrophysiology. Together, our findings identify disrupted progenitor communication as an early developmental consequence of SCN1A haploinsufficiency and suggest that abnormalities within neural progenitor populations contribute to altered corticogenesis, excitatory neurogenesis, and circuit hyperexcitability in Dravet syndrome. This work expands current disease models beyond interneuron dysfunction and highlights the developing ventricular zone as a potential therapeutic target.

neuroscience↗

bioRxiv2024

Human transferrin and lactoferrin cooperatively support Neisseria meningitidis colonization in the murine nasopharynx

Neisseria meningitidis is a human-restricted bacteria that is a normal nasopharyngeal resident, yet it can also disseminate, causing invasive meningococcal disease. Meningococci are highly adapted to life in humans, with human-specific virulence factors contributing to bacterial adhesion, nutrient acquisition and immune evasion. While these factors have been explored in isolation, their relative contribution during infection has not been considered due to their absence in small animal models and their expression by different human cell types not readily combined in either in vitro or ex vivo systems. Herein, we show that transgenic expression of the iron-binding glycoproteins human transferrin and lactoferrin can each facilitate N. meningitidis replication in mouse serum but that transferrin was required to support infection-induced sepsis. While these host proteins are insufficient to allow nasopharyngeal colonization alone, mice co-expressing these and human CEACAM1 support robust colonization. In this case, meningococcal colonization elicits an acute elevation in both transferrin and lactoferrin levels within the upper respiratory mucosa, with transferrin levels remaining elevated while lactoferrin returns to basal levels after establishment of infection. Competitive infection of triple transgenic animals with transferrin- and lactoferrin- binding protein mutants selects for bacteria expressing the transferrin receptor, implicating the critical contribution of transferrin-based iron acquisition to support colonization. These transgenic animals have thus allowed us to disentangle the relative contribution of three virulence factors during colonization and invasive disease, and provides a novel in vivo model that can support extended meningococcal colonization, opening a new avenue to explore the meningococcal lifestyle within its primary niche.

microbiology↗

bioRxiv2019

Reversible Mitochondrial Fragmentation in iPSC-Derived Cardiomyocytes from Children with DCMA, a Mitochondrial Cardiomyopathy

BackgroundThe dilated cardiomyopathy with ataxia syndrome (DCMA) is an understudied autosomal recessive disease caused by loss-of-function mutations in the poorly characterized gene DNAJC19. Clinically, DCMA is commonly associated with heart failure and early death in affected children through an unknown mechanism. DCMA has been linked to Barth syndrome, a rare but well-studied disorder caused by deficient maturation of cardiolipin (CL), a key mitochondrial membrane phospholipid.\n\nMethodsPeripheral blood mononuclear cells from two children with DCMA and severe cardiac dysfunction were reprogrammed into induced pluripotent stem cells (iPSCs). Patient and control iPSCs were differentiated into beating cardiomyocytes (iPSC-CMs) using a metabolic selection strategy and mitochondrial structure and CL content before and after incubation with the mitochondrially-targeted peptide SS-31 were quantified.\n\nResultsPatient iPSCs carry the causative DNAJC19 mutation (rs137854888) found in the Hutterite population and the iPSC-CMs demonstrated highly fragmented and abnormally-shaped mitochondria associated with an imbalanced isoform ratio of the mitochondrial protein OPA1, an important regulator of mitochondrial fusion. These abnormalities were reversible by incubation with SS-31 for 24 hours. Differentiation of iPSCs into iPSC-CMs increased the number of CL species observed but consistent, significant differences in CL content were not seen between patients and control.\n\nConclusionsWe describe a unique and novel cellular model that provides insight into the mitochondrial abnormalities present in DCMA and identifies SS-31 as a potential therapeutic for this devastating disease.

cell biology↗