Biology subjects

Haydar, T. F.

Publications and source records attributed to Haydar, T. F..

4 recordsLinked to original sources

bioRxiv2025

A humanized mouse model system mimics prenatal Zika infection and reveals premature differentiation

Zika, a mosquito-borne flavivirus, has been found in 87 countries and territories. Global outbreaks peaked in 2016. Prenatal infection of Zika virus was found to be associated with microcephaly, arthrogryposis, intracranial calcifications, fetal growth restriction, and fetal demise. The most severely affected children were diagnosed with congenital Zika syndrome, which impacts thousands worldwide. With no approved treatment or preventative measures for Zika, future viral outbreaks have the potential to cause epidemic levels of prenatal brain injury, as seen over the past 70 years. Therefore, there is a great need for a reliable and clinically translational experimental system that mimics the human condition of prenatal Zika infection. To this end, we developed a humanized, immunocompetent mouse model system of virally induced brain injury from prenatal Zika infection, which ranges from mild to severe. Here, we describe the extent to which this system mirrors the human phenotypic spectrum. Using our thorough preclinical system, we find that prenatal Zika infection of mice impacts survival rate, anthropometric measurements, tissue formation, and neurological outcomes, all of which are typical of prenatal infection. Single-cell RNA sequencing of the Zika-infected cerebral cortex reveals severely disrupted transcriptome profiles and suggests that these injuries are a result of a depletion of neural stem cells. Current and future applications include the identification of genetic or environmental modifiers of brain injury, molecular or mechanistic studies of pathogenesis, and preclinical evaluation of future therapies.

neuroscience↗

bioRxiv2024

MuMu: a sample multiplexing protocol for droplet-based simultaneous single nuclei RNA- and ATAC-seq systems

Sample multiplexing is a common approach to reduce experimental cost and technical batch effect. Here, we present a protocol that for the first time allows the pooling of single nuclei from multiple biological samples prior to performing simultaneous single nuclei RNA-seq and ATAC-seq, which we term Multiplexed Multiome (MuMu). We describe steps for assembling the custom Tn5 transposome, performing the transposition reaction, nuclei pooling, sequencing library preparation, and sequencing data pre-processing. This protocol will greatly reduce the cost of sn-Multiome. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=163 HEIGHT=200 SRC="FIGDIR/small/625728v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@19d7962org.highwire.dtl.DTLVardef@18c1c04org.highwire.dtl.DTLVardef@18355a9org.highwire.dtl.DTLVardef@16cdb6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2024

Ciliopathy interacts with neonatal anesthesia to cause non-apoptotic caspase-mediated motor deficits

Increasing evidence suggests that anesthesia may induce developmental neurotoxicity, yet the influence of genetic predispositions associated with congenital anomalies on this toxicity remains largely unknown. Children with congenital heart disease often exhibit mutations in cilia-related genes and ciliary dysfunction, requiring sedation for their catheter or surgical interventions during the neonatal period. Here we demonstrate that briefly exposing ciliopathic neonatal mice to ketamine causes motor skill impairments, which are associated with a baseline deficit in neocortical layer V neuron apical spine density and their altered dynamics during motor learning.. These neuromorphological changes were linked to augmented non-apoptotic neuronal caspase activation. Neonatal caspase suppression rescued the spine density and motor deficits, confirming the requirement for sublethal caspase signaling in appropriate spine formation and motor learning. Our findings suggest that ciliopathy interacts with ketamine to induce motor impairments, which is reversible through caspase inhibition. Furthermore, they underscore the potential for ketamine- induced sublethal caspase responses in shaping neurodevelopmental outcomes.

neuroscience↗

bioRxiv2022

Asynchronous excitatory neuron development in an isogenic cortical spheroid model of Down syndrome

The intellectual disability (ID) in Down syndrome (DS) is thought to result from a variety of developmental deficits such as alterations in neural progenitor division, neurogenesis, gliogenesis, cortical architecture, and reduced cortical volume. However, the molecular processes underlying these neurodevelopmental changes are still elusive, preventing an understanding of the mechanistic basis of ID in DS. In this study, we used a pair of isogenic (trisomic and euploid) induced pluripotent stem cell (iPSC) lines to generate cortical spheroids (CS) that model the impact of trisomy 21 on brain development. CS contain neurons, astrocytes, and oligodendrocytes and they are widely used to approximate early neurodevelopment. Using single cell RNA sequencing (scRNA-seq), we uncovered cell type-specific transcriptomic changes in the trisomic CS. In particular, we found that excitatory neuron populations were most affected and that a specific population of cells with a transcriptomic profile resembling layer IV cortical neurons displayed the most profound divergence in developmental trajectory between trisomic and euploid genotypes. We also identified candidate genes potentially driving the developmental asynchrony between trisomic and euploid excitatory neurons. Direct comparison between the current isogenic CS scRNA-seq data and previously published datasets revealed several recurring differentially expressed genes between DS and control samples. Altogether, our study highlights the power and importance of cell type-specific analyses within a defined genetic background, coupled with broader examination of mixed samples, to comprehensively evaluate cellular phenotypes in the context of DS.

neuroscience↗