Biology subjects

Tsuruta, F.

Publications and source records attributed to Tsuruta, F..

4 recordsLinked to original sources

bioRxiv2024

Perinatal Reduction of Genetically Aberrant Neurons from Human Cerebral Cortex

Human neurons are postmitotic and long-lived, requiring precise genomic regulation to maintain function over a lifetime. Normal neuronal function is highly dependent on gene dosage, with copy number variants (CNVs) and heterozygous point mutations associated with a host of neurodevelopmental and neuropsychiatric conditions [1-5]. Here, we investigated the landscape of somatic CNVs arising in fetal human brains, and how they change over development, to understand the processes that generate normal neuronal genomes. We sequenced 2,158 single neurons from human postmortem brain using two distinct single cell whole genome sequencing (scWGS) approaches. Tn5-transposase based (TbA) scWGS of 1,327 neurons from 16 individuals ranging in age from gestational week 14 to 90 years old resulted in 8,765 CNVs. Primary template amplification (PTA) was used to assess for CNV from 831 neurons from 12 individuals. Up to 46% of neurons in prenatal cortex showed aberrant genomes, characterized by widespread CNVs of multiple chromosomes, but this proportion reduces by 4-5 fold after birth across the two scWGS approaches (p=7.5x10-6, Fisher meta-analysis). We identified micronuclei in the developing cortex in situ, reflecting chromosomal material missegregated during neurodevelopment [6-8]. Neurons with widespread CNVs were eliminated in the perinatal period, while neurons with smaller CNV burden slowly declined during postnatal aging. CNVs in surviving neurons were depleted for genes that are dosage-sensitive or involved in neurodevelopmental disorders (p<0.05), suggesting selective elimination of neurons with CNVs involving these critical genes. We surveyed 44,861 nuclei with 10X Genomics scATAC/RNAseq and determined that neurons with high CNV burdens also showed abnormal expression of synaptic gene sets, suggesting that abnormal synaptic gene regulation contributes to neuronal elimination. Elimination of defective neuronal genomes during synaptogenesis may represent a critical process of genome quality control and a vulnerable target of factors that contribute to neurodevelopmental disease.

neuroscience↗

bioRxiv2023

Propagation of neuronal micronuclei regulates microglial states

Microglia, resident immune cells in the central nervous system, undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial development and maturation remain largely unknown. In this study, we show that neuronal micronuclei propagate microglia, followed by changing microglial states during the postnatal period. We discovered that neurons passing through a dense region of the developing neocortex give rise to micronuclei and release them into the extracellular space. Moreover, neuronal micronuclei were incorporated into microglia and affected morphological changes. Loss of the cGAS gene alleviates effects on micronucleus-dependent morphological changes. Notably, neuronal micronuclei-harboring microglia exhibit unique transcriptome signatures. These results demonstrate that neuronal micronuclei serve as niche signals that produce novel microglial states. Our findings provide a potential mechanism for regulating the microglial state in the early-postnatal neocortex.

neuroscience↗

bioRxiv2023

RBM3 deficiency impairs body temperature control in response to cold stimulation

Mammals are thermostatic animals capable of regulating their body temperature within a precise range, irrespective of ambient temperature conditions. However, the precise mechanisms by which a body temperature is controlled dependent on ambient temperature are still unclear. Here, we report that RNA binding motif protein 3 (RBM3), one of the cold-responsive proteins, regulates body temperature via expressing thermogenic genes during the late-postnatal period. The body temperature in Rbm3 knockout (KO) juvenile mice was unstable and increased vulnerability to cold exposure. In addition, Rbm3 KO mice exhibited increased lipid droplets in brown adipose tissue (BAT) and abnormal histology. The single-cell RNA-seq (scRNA-seq) analysis revealed that RBM3 is highly expressed in proliferating and differentiating cells in BAT. Moreover, RBM3 was necessary for upregulating thermogenic genes after cold shock. Notably, RBM3 interacted with UCP1 mRNA in vivo, thereby stabilizing its mRNA levels. Lastly, RBM3 regulated neuronal activity in the dorsomedial hypothalamic nucleus (DMH) under a cold environment. These data suggest that RBM3 regulates thermogenesis in juvenile mice through both upregulating thermogenic genes in BAT and activating DMH neurons after cold exposure.

physiology↗

bioRxiv2022

Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability

Hevin is a secreted extracellular matrix protein that is encoded by SPARCL1 gene. Recent studies show that Hevin plays an important role in regulating synaptogenesis and synaptic plasticity. Mutations in SPARCL1 gene increase the risk of autism spectrum disorder (ASD). However, the molecular basis of how mutations in SPARCL1 increase the risk of ASD has not been fully understood. In this study, we show that one of SPARCL1 mutations associated with ASD impairs normal Hevin secretion. We identified Hevin mutants lacking the EF-hand motif through analyzing ASD-related mice with vulnerable spliceosome functions. Hevin deletion mutants accumulate in the ER, leading to the activation of unfolded protein responses. We also found that a single amino acid substitution of Trp647 with Arg in the EF-hand motif associated with a familial case of ASD causes a similar phenotype with the EF-hand deletion mutant. Importantly, molecular dynamics (MD) simulation revealed that this single amino acid substitution triggers exposure of hydrophobic amino acid to the surface, increasing the binding of Hevin with a molecular chaperon, BIP. Taken together, these data suggest that the integrity of EF-hand motif in Hevin is crucial for proper folding and ASD-related mutation impairs an export of Hevin from the endoplasmic reticulum (ER). Our data provide a novel mechanism linking a point mutation in SPARCL1 gene to the molecular and cellular characteristics involved in ASD.

molecular biology↗