Biology subjects

Peer, A.

Publications and source records attributed to Peer, A..

7 recordsLinked to original sources

bioRxiv2026

A Closed Computational - Experimental Loop Identifies Metabolic Collapse at the Root of Macrophage Dysfunction due to Zinc Dyshomeostasis

Zinc plays a crucial role in immune regulation, the oxidative stress response, and epithelial barrier integrity, yet zincs precise role in regulating metabolic and immunological functions in myeloid cells remains poorly understood. Here, we employ a systems biology approach using constraint-based modeling to elucidate the consequences of myeloid-specific loss of ZIP8 on macrophage metabolic function and antibacterial capabilities. We demonstrate that macrophage populations in the lung of ZIP8 knockout (Zip8KO) mice exhibit widespread metabolic disruption, spanning glycolysis, butanoate metabolism, amino acid metabolism, and mitochondrial function. Specifically, Zip8KO macrophages exhibit impaired nutrient uptake and dysregulated energy metabolism, which is exacerbated following Streptococcus pneumoniae infection. Genome-scale metabolic modeling and flux analysis revealed a paradoxical pattern of metabolic suppression prior to infection, followed by overcompensation post-infection, potentially driving immune dysfunction. Consistent with these predictions Zip8KO bone marrow-derived macrophages displayed increased ATP demand and disrupted mitochondrial energetics, compromising their ability to control infection. Importantly, we identified succinate, and kynurenic acid as metabolites capable of restoring immune responses and validated their ability to enhance bacterial clearance in Zip8KO BMDMs. Together, these findings establish ZIP8 as a central regulator of immune-metabolic homeostasis and suggest potential therapeutic avenues to restore immune function in settings of zinc deficiency.

immunology↗

bioRxiv2025

Meiosis-specific genes play roles in ploidy reduction in Cryptococcus neoformans titan cells

Cryptococcus neoformans is a fungal pathogen of humans that causes life-threatening meningoencephalitis. During infection, enlarged, polyploid titan cells are produced that promote persistence in the host, in part by resisting phagocytosis; under stress conditions, such as exposure to the antifungal drug fluconazole, titan cells can produce aneuploid or diploid, drug-resistant daughter cells. However, the mechanism underlying this ploidy reduction remains poorly understood. Interestingly, meiosis related genes have been shown to be activated during Cryptococcus infection, leading us to hypothesize that the depolyploidization of C. neoformans titan cells may occur through a process resembling the ploidy reduction during meiosis. In this study, we show that titan cells developed from diploid strains predominantly produce diploid daughter cells with haploid daughters observed infrequently. We further demonstrate that meiosis-specific genes, including DMC1 and SPO11, are critical for stable inheritance of a diploid genome in the daughter cells. Specifically, deletion of these genes in a heterozygous diploid background resulted in: 1) titan cells with a significantly reduced capacity to produce daughter cells; 2) increased phenotypic variation among daughter cells produced by the titan cells, including traits that could be relevant to cell growth and viability; and 3) daughter cells produced by the titan cells exhibiting high levels of loss of heterozygosity (LOH) and aneuploidy, suggesting elevated genome instability. Taken together, these findings demonstrate the importance of meiosis-specific genes in the ploidy reduction process of titan cells derived from a heterozygous diploid background in an important human fungal pathogen. SIGNIFICANCEPolyploid titan cells are central to Cryptococcus neoformans persistence during infection, yet how they reduce ploidy to generate daughter cells was unclear. In most eukaryotes, the meiosis-related proteins Spo11 and Dmc1 are best known for initiating (double-strand break formation) and executing (strand exchange) meiotic recombination, respectively. Here, we show that in C. neoformans, Dmc1 and Spo11 are critical for polyploid titan cells to produce viable daughter cells with reduced ploidy specifically in a heterozygous diploid context, ensuring genome stability without introducing detectable canonical meiotic recombination. Loss of either gene compromises daughter cell production and causes genome instability (LOH, aneuploidy) and phenotypic heterogeneity. These findings reveal a "para-meiosis" safeguard that preserves genomic configurations during titan cell depolyploidization in C. neoformans.

genetics↗

bioRxiv2024

Essential genes encoded by the mating-type locus of the human fungal pathogen Cryptococcus neoformans

Fungal sexual reproduction is controlled by the mating-type (MAT) locus. In contrast to a majority of species in the phylum Basidiomycota that have tetrapolar mating-type systems, the opportunistic human pathogen Cryptococcus neoformans employs a bipolar mating-type system, with two mating types (a and ) determined by a single MAT locus that is unusually large ([~]120 kb) and contains more than 20 genes. While several MAT genes are associated with mating and sexual development, others control conserved cellular processes (e.g. cargo transport and protein synthesis), of which five (MYO2, PRT1, RPL22, RPL39, and RPO41) have been hypothesized to be essential. In this study, through genetic analysis involving sporulation of heterozygous diploid deletion mutants, as well as in some cases construction and analyses of conditional expression alleles of these genes, we confirmed that with the exception of MYO2, both alleles of the other four MAT genes are indeed essential for cell viability. We further showed that while MYO2 is not essential, its function is critical for infectious spore production, faithful cytokinesis, adaptation for growth at high temperature, and pathogenicity in vivo. Our results demonstrate the presence of essential genes in the MAT locus that are divergent between cells of opposite mating types. We discuss possible mechanisms to maintain functional alleles of these essential genes in a rapidly-evolving genomic region in the context of fungal sexual reproduction and mating-type evolution. IMPORTANCESexual reproduction is essential for long-term evolutionary success. Fungal cell type identity is governed by the MAT locus, which is typically rapidly evolving and highly divergent between different mating types. In this study, we show that the a and alleles of four genes encoded in the MAT locus of the opportunistic human fungal pathogen C. neoformans are essential. We demonstrate that a fifth gene, MYO2, which had been predicted to be essential, is in fact dispensable for cell viability. However, a functional MYO2 allele is important for cytokinesis and fungal pathogenicity. Our study highlights the need for careful genetic analyses in determining essential genes, which is complementary to high-throughput approaches. Additionally, the presence of essential genes in the MAT locus of C. neoformans provides insights into the function, maintenance, and evolution of these fast-evolving genomic regions.

genetics↗

bioRxiv2023

ARID1B controls transcriptional programs of axon projection in the human corpus callosum

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC). This condition is characterized by a partial or complete absence of the corpus callosum (CC), an interhemispheric white matter tract that connects distant cortical regions. Using human neural organoids, we identify a vulnerability of callosal projection neurons (CPNs) to ARID1B haploinsufficiency, resulting in abnormal maturation trajectories and dysregulation of transcriptional programs of CC development. Through a novel in vitro model of the CC tract, we demonstrate that ARID1B mutations reduce the proportion of CPNs capable of forming long-range projections, leading to structural underconnectivity phenotypes. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous defects in axonogenesis as a cause of ACC in ARID1B patients. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/539362v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@dd4e9aorg.highwire.dtl.DTLVardef@153a081org.highwire.dtl.DTLVardef@14e884corg.highwire.dtl.DTLVardef@d64081_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO Human callosal projection neurons are vulnerable to ARID1B haploinsufficiency. (Top) During healthy development, callosal projection neurons (CPNs) project long interhemispheric axons, forming the corpus callosum (CC) tract, which can be modeled in vitro. (Bottom) In ARID1B patients, transcriptional dysregulation of genetic programs of CC development reduces the formation of long-range projections from CPNs, causing CC agenesis in vivo and underconnectivity phenotypes in vitro. C_FIG

neuroscience↗

bioRxiv2022

Morphogenesis and development of human telencephalic organoids in the absence and presence of exogenous ECM

Establishment and maintenance of apical-basal polarity is a fundamental step in brain development, instructing the organization of neural progenitor cells (NPCs) and the developing cerebral cortex. Particularly, basally located extracellular matrix (ECM) is crucial for this process. In vitro, epithelial polarization can be achieved via endogenous ECM production, or exogenous ECM supplementation. While neuroepithelial development is recapitulated in cerebral organoids, the effects of different ECM sources in tissue morphogenesis remain unexplored. Here, we show that exposure to exogenous ECM at early neuroepithelial stages causes rapid tissue polarization and complete rearrangement of neuroepithelial architecture within 3 days. In unexposed cultures, endogenous ECM production by NPCs results in gradual polarity acquisition over an extended time. After the onset of neurogenesis, tissue architecture and neuronal differentiation are largely independent of the initial ECM source. These results advance the knowledge on neuroepithelial biology in vitro, with a focus on mechanisms of exogenously- and endogenously-guided morphogenesis. They demonstrate the self-sustainability of neuroepithelial cultures by endogenous processes, prompting an urgent reassessment of indiscriminate use of exogenous ECM in these model systems.

developmental biology↗

bioRxiv2020

Gait-level analysis of mouse open field behavior using deep learning-based pose estimation

1Gait and whole body posture are sensitive measures of the proper functioning of numerous neural circuits, and are often perturbed in many neurological, neuromuscular, and neuropsychiatric illnesses. Rodents provide a tractable model for elucidating disease mechanisms and interventions, however, studying gait and whole body posture in rodent models requires specialized methods and remains challenging. Here, we develop a simple assay that allows adoption of the commonly used open field apparatus for gait and whole body posture analysis. We leverage modern neural networks to abstract a mouse into keypoints and extract gait and whole body coordination metrics of the animal. Gait-level analysis allows us to detect every step of the animals movement and provides high resolution information about the animals behavior. We quantitate gait and whole body posture with high precision and accuracy across 62 highly visually diverse strains of mice. We apply our approach to characterize four genetic mutants with known gait deficits. In extended analysis, we demonstrate that multiple autism spectrum disorder (ASD) models show gait and posture deficits, implying this is a general feature of ASD. We conduct a large strain survey of 1898 mice, and find that gait and whole body posture measures are highly heritable in the laboratory mouse, and fall into three classes. Furthermore, the reference mouse strain, C57BL/6J, has a distinctly different gait and posture compared to other standard laboratory and wild-derived strains. We conduct a genome wide association study (GWAS) to define the genetic architecture of mouse movement in the open field. In sum, we describe a simple, sensitive, accurate, scalable, and ethologically relevant method of mouse gait and whole body posture analysis for behavioral neurogenetics. These results provide one of the largest laboratory mouse gait-level data resources for the research community and show the utility of automated machine learning approaches for deriving biological insights.

animal behavior and cognition↗

bioRxiv2020

Action detection using a neural network elucidates the genetics of mouse grooming behavior

Automated detection of complex animal behaviors remains a challenging problem in neuroscience, particularly for behaviors that consist of disparate sequential motions. Grooming, a prototypical stereotyped behavior, is often used as an endophenotype in psychiatric genetics. Using mouse grooming behavior as an example, we develop a general purpose neural network architecture capable of dynamic action detection at human observer-level performance and operate across dozens of mouse strains with high visual diversity. We provide insights into the amount of human annotated training data that are needed to achieve such performance. We survey grooming behavior in the open field in 2500 mice across 62 strains, determine its heritable components, conduct GWAS to outline its genetic architecture, and perform PheWAS to link human psychiatric traits through shared underlying genetics. Our general machine learning solution that automatically classifies complex behaviors in large datasets will facilitate systematic studies of mechanisms underlying these behaviors.

bioinformatics↗