Biology subjects

Fernandez Garcia, M.

Publications and source records attributed to Fernandez Garcia, M..

4 recordsLinked to original sources

bioRxiv2026

Estradiol modulates neuronal network hyperexcitability in select NDD risk genes

Sex hormone signaling during neurodevelopment may act as a modulator of risk for neurodevelopmental disorders (NDDs), including autism spectrum disorders (ASDs). By conducting a systematic and multi-modal evaluation of estradiol effects across loss-of-function deletions in 36 functionally diverse, large-effect ASD/NDD genes in human induced pluripotent stem cell-derived neurons and larval zebrafish, we uncover convergent and divergent gene-by-estradiol interactions at the transcriptomic, circuit, and behavioral levels. Whereas estradiol partially ameliorates dysregulated expression signatures across all ASD/NDD gene knockouts examined, it selectively and rapidly dampens network hyperexcitability phenotypes in only a subset of ASD/NDD gene knockouts. Two genes, ASH1L and SCN2A, are particularly responsive to estradiol treatment, with dramatic rescue of molecular and cellular effects in human knockout neurons, coupled with behavioral phenotypes in larval zebrafish mutants. The seven most estradiol responsive genes show enhanced protein-protein interaction network connectivity, strong co-expression in specific postnatal time periods, and enrichment in upper-layer mature excitatory neurons. Altogether, we describe distinct estradiol rescue in different modalities, elucidating shared transcriptomic effects as well as gene-specific cellular and behavioral rescue in the context of loss of function mutations of select ASD/NDD genes.

genomics↗

bioRxiv2024

A lipid transport Mla Pqi Chimeric system is essential for Brucella abortus survival in macrophages

The envelope of diderm bacteria comprises of an inner membrane (IM) and an outer membrane (OM). Several pathways have been recently identified that facilitate the transport of phospholipids between the two membranes in Escherichia coli, including maintaining OM lipid asymmetry (Mla) and paraquat inducible (Pqi) systems. In this study, we report the identification and the characterization of a complex named Mpc in the intracellular pathogen Brucella abortus. Mpc is conserved in numerous species of Hyphomicrobiales and exhibits homology to both the Mla and Pqi systems. Mpc is essential for bacterial growth under conditions of envelope stress and for survival within macrophages during the early stages of infection. Analyses of protein-protein interactions and structural predictions indicate that the Mpc complex bridges IM to OM. The absence of this system results in an altered lipid composition of the OM vesicles, supporting the fact that Mpc plays a role in the transport of lipids between membranes. The discovery of a novel lipid trafficking system enhances the diversity and complexity of known lipid trafficking systems within diderm bacteria.

microbiology↗

bioRxiv2024

Dynamic convergence of autism disorder risk genes across neurodevelopment

Over three hundred and seventy-three risk genes, broadly enriched for roles in neuronal communication and gene expression regulation, underlie risk for autism spectrum disorder (ASD) and developmental delay (DD). Functional genomic studies of subsets of these genes consistently indicate a convergent role in neurogenesis, but how these diverse risk genes converge on a smaller number of biological pathways in mature neurons is unclear. To uncover shared downstream impacts between neurodevelopmental disorder (NDD) risk genes, here we apply a pooled CRISPR approach to contrast the transcriptomic impacts of targeting 29 NDD loss-of-function genes across human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Points of convergence vary between the cell types of the brain and are greatest in mature glutamatergic neurons, where they broadly target not just synaptic and epigenetic, but unexpectedly, mitochondrial biology. The strongest convergent networks occur between NDD genes with common co-expression patterns in the post-mortem brain, biological annotations, and clinical associations, suggesting that convergence may one-day inform patient stratification and treatment. Towards this, ten out of eleven drugs tested that were predicted to reverse convergent signatures in human cells and/or arousal and sensory processing behaviors in zebrafish ameliorated at least one behavioral phenotype in vivo. Altogether, robust convergence in post-mitotic neurons represents a clinically actionable therapeutic window.

genetics↗

bioRxiv2020

Common genetic variation in humans impacts in vitro susceptibility to SARS-CoV-2 infection

The host response to SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, demonstrates significant inter-individual variability. In addition to showing more disease in males, the elderly, and individuals with underlying co-morbidities, SARS-CoV-2 can seemingly render healthy individuals with profound clinical complications. We hypothesize that, in addition to viral load and host antibody repertoire, host genetic variants also impact vulnerability to infection. Here we apply human induced pluripotent stem cell (hiPSC)-based models and CRISPR-engineering to explore the host genetics of SARS-CoV-2. We demonstrate that a single nucleotide polymorphism (rs4702), common in the population at large, and located in the 3UTR of the protease FURIN, impacts alveolar and neuron infection by SARS-CoV-2 in vitro. Thus, we provide a proof-of-principle finding that common genetic variation can impact viral infection, and thus contribute to clinical heterogeneity in SARS-CoV-2. Ongoing genetic studies will help to better identify high-risk individuals, predict clinical complications, and facilitate the discovery of drugs that might treat disease.

cell biology↗