Biology subjects

Saeki, M.

Publications and source records attributed to Saeki, M..

4 recordsLinked to original sources

bioRxiv2026

Postweaning social isolation induces gene expression alterations and histone modification dysregulations in nucleus accumbens (NAc) neurons

Lack of social interaction results in various behavioral abnormalities in rodents, including increased anxiety levels, altered sociability, and impaired cognitive ability. Epigenetic factors regulate gene expression, however, how they are involved in juvenile social isolation (jSI)-induced behavioral alterations remains largely unknown. Here, we focused on the nucleus accumbens (NAc), a critical brain region of the reward system that regulates motivation-related behaviors. We first performed RNA-seq on neuronal nuclei and found alterations in genes related to neuronal function, as well as in transcriptional and epigenetic regulation. Protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) showed that top key nodes among down-regulated genes include membrane receptors (Ntrk2, Grin3a, and Grik1) and an apoptosis regulator (Bcl2). To further investigate the association between jSI-induced gene expression alterations and histone modifications, we next performed CUT&Tag for four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3), and the results implied that epigenetic alterations may also play a role in neuronal function as well as transcriptional regulation. Reanalysis of previously published RNA-seq data on the manipulation of histone modification-associated factors (including Kdm6b, Brd4, and Setd1a) suggested that these enzymes are candidate regulators of jSI-induced gene expression alterations. Taken together, our comprehensive analysis characterizes the association between histone modification and jSI-related alterations of gene expression in the NAc of female mice.

neuroscience↗

bioRxiv2025

Sex-biased transcriptome in embryonic mouse cortices under Pax6 haploinsufficiency highlights Pbdc1 as a candidate regulator

Mutations in Pax6, encoding a transcription factor essential for brain patterning and neurogenesis, have been linked to female-biased cortical malformations and behavioral abnormalities, yet the molecular basis remains unclear. Here we show that Pax6 haploinsufficiency (Sey/+) produces more pronounced sex-biased alterations in the transcriptomes and cytoarchitecture of embryonic mouse cortices than those in wild-type and homozygous mutants (Sey/Sey). Pbdc1, a previously uncharacterized X-linked gene implicated in autism, is selectively upregulated in Sey/+ females and proximity-dependent protein-protein interaction analysis reveals Pbdc1 interacts with RNA-splicing factors. Moreover, Pbdc1 overexpression reduces intermediate progenitor cells in the developing cortex. ChIP-qPCR further demonstrates Pax6 and BAF occupancy at the Pbdc1 promoter in WT embryos of both sexes and CUT&Tag shows H3K4me3 elevation selectively in Sey/+ females. Our findings indicate that partial loss of Pax6 shapes the embryonic cortical transcriptomes and cytoarchitecture in a sex-dependent manner and highlight Pbdc1 as a candidate regulator of sex-biased corticogenesis.

developmental biology↗

bioRxiv2025

Neuronal migration induces DNA damage in developing brain

Migratory cells tend to have soft nuclei that deform and penetrate narrow spaces1,2. Extensive nuclear deformation during migration can cause nuclear envelope rupture and DNA damage in cancer cells, which may contribute to the malignant transformation during tumor progression3,4,5,6. However, the significance of DNA damage in physiological migration is less well understood. Here, we demonstrate that the migration of neurons in developing cerebral and cerebellar cortices is accompanied by massive DNA double-strand breaks (DSBs) due to mechanostress during passage through narrow interstitial spaces. Confined migration enhances the binding and cleavage of the genome by topoisomerase II{beta}, expressed in neuronal nucleus, independently of the nuclear envelope rupture. Genome sequencing revealed that DSBs tend to occur outside of protein-coding regions and transcription regulatory regions. During normal development, DSBs are rapidly repaired by the non-homologous end joining pathway. The deletion of ligase IV at the onset of neuronal migration leads to persistent DSB accumulation in cerebellar neurons with moderate transcriptional changes in genes related to synaptic function, neuronal development, and stress and immune responses. The mutant mouse develops mild motor deficits in later life, suggesting that the DNA damage generated during normal brain development poses a potential disease risk if left unrepaired.

cell biology↗

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↗