Department of Pediatrics/Rady Children's Hospital, Department of Cellular & Molecular Medicine, University of California San Diego, School of Medicine, La Jolla, CA, 92037, USA.
Published: April 2023
AI Article Synopsis
Article Abstract
Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.
Experimental neuroscience techniques are advancing rapidly, with major recent developments in high-density electrophysiology and targeted electrical stimulation. In combination with these techniques, cortical organoids derived from pluripotent stem cells show great promise as models of brain development and function. Although sensory input is vital to neurodevelopment , few studies have explored the effect of meaningful input to neural cultures over time.
A growing number of therapies are being developed to target the cell cycle machinery for the treatment of cancer and other human diseases. Consequently, a greater understanding of the factors regulating cell cycle progression becomes essential to help enhance the response to these new therapies. Here, using data from the Cancer Dependency Map, we identified the poorly-studied factor FAM53C as a new regulator of cell cycle progression.
Introduction: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC).
Methods: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.
Taybi-Linder syndrome (TALS) is a rare autosomal recessive disorder characterized by severe microcephaly with abnormal gyral pattern, severe growth retardation and bone abnormalities. It is caused by pathogenic variants in the RNU4ATAC gene. Its transcript, the small nuclear RNA U4atac, is involved in the excision of ~850 minor introns.
Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell (hESC)-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later.
