大野 伸彦

Mossy fiber (MF)-CA3 synapses in the hippocampus play vital roles in learning and memory. MFs have characteristic giant boutons with thorny excrescences on the dendrites of CA3 pyramidal neurons. The mechanisms underlying the development of this complex synaptic specialization remain unclear. In the present study, the loss of synaptosomal-associated protein 25 (SNAP25)-a protein essential for regulated synaptic vesicular release-increased the density but decreased the size of MF boutons and altered the postsynaptic distribution of homer scaffolding protein 1. Three-dimensional correlative light and electron microscopy revealed that although axon targeting and synapse formation were unaffected, excrescences failed to develop in MF boutons, resulting in a smaller contact area between MF boutons and CA3 dendrites. Moreover, SNAP25-deficient boutons displayed abnormal intracellular profiles, such as the accumulation of large synaptic vesicles. These findings indicate that presynaptic SNAP25 is essential for the maturation and maintenance of specialized hippocampal giant boutons.

Retinal organoids represent a promising regenerative strategy for restoring vision in retinal degenerative diseases, but the capacity of host cone bipolar cells in the primate macula to rewire with transplanted photoreceptors has not been established. In this study, we transplanted genome-edited ISL1-/- human retinal organoids lacking ON-bipolar cells into an acute laser-induced macular photoreceptor ablation nonhuman primate model. Using immunohistochemistry, ultrastructural imaging, and focal macular electroretinography (FMERG), we demonstrate that host rod and cone bipolar cells actively extend dendrites toward grafted photoreceptors and form synaptic contacts, with evidence of functional signal transmission in a subset of transplanted eyes. Longitudinal, per-eye analyses revealed that host ON-bipolar responses improved in two of four eyes with ISL1-/- graft by up to 21.6% and remained stable for up to 2 years post-transplantation. Moreover, OFF-pathway connectivity showed potential progressive maturation, with delayed increase in d-wave after 13 months in one of those eyes. These findings provide the first demonstration of long-term anatomical host-graft synaptic integration in the primate macula, establishing that central cone bipolar circuits retain the capacity for durable rewiring with human stem cell-derived grafts. Our results highlight ISL1-/- retinal organoids as a promising approach for central vision restoration in macular degeneration.

The molecular mechanisms underlying metastasis still remain unclear. We previously established a suspension culture using low-attachment culture dishes and demonstrated that cell lines adapted through 2 months suspension culture (termed FL sublines) exhibited higher metastatic potential than their parental counterparts. In this study, we identified the molecules involved in acquiring these phenotypes under low-adhesion conditions. We showed that detached tumor cells in suspension culture formed spheroids that recapitulated tumor cells in the spread-through-air space (STAS), and demonstrated that the anti-adhesion molecule mucin 21 was upregulated in detached lung cancer cells independent of driver mutations. Analyses of both cell lines and primary tumors revealed that mucin 21 is overexpressed in terminal respiratory unit-type lung adenocarcinomas. Mucin 21-knockout cells showed reduced viability and proliferation under adherent and low-attachment conditions, accompanied by enhanced anoikis. Transmission electron microscopy revealed that the intercellular spaces observed in FL sublines during suspension culture were reduced in mucin 21-knockout cells, suggesting impaired acquisition of low adhesive properties. Thus, mucin 21 appears crucial for the survival of terminal respiratory unit-type lung adenocarcinoma cells under both adherent and low-adhesion conditions.

CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and c.2689 A > T,p.(K897*), in a microcephalic patient and analyzed them alongside a homozygous variant c.95 A > C,p.(Q32P) associated with severe microcephaly with marked gyral simplification. In vitro assays revealed distinct effects: p.K897* prevented centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal targeting but disrupted binding to Polo-like kinase 4, a key centriole biogenesis kinase and CEP152 partner. In vivo, both Cep152W105*/K897* and Cep152Q32P/Q32P knock-in mice displayed microcephaly; notably, Cep152Q32P/Q32P mice also exhibited severe cortical defects during brain development. Cellular analyses revealed centrosome dysfunction, mitotic errors, and increased apoptosis, which were exacerbated in Cep152Q32P/Q32P brains. Morphological examination, including electron microscopy, further demonstrated structural abnormalities of the centrosomes and centrioles in Cep152Q32P/Q32P brains. Electrophysiological and gene expression analyses confirmed variant-specific neuronal impairments, which correlate with clinical severity. Collectively, these findings demonstrate that distinct CEP152 variants disrupt neurodevelopment through different mechanisms, thereby explaining the spectrum of microcephaly severity and associated phenotypes.

Human activities increasingly disrupt global ecosystems, contributing to climate change, biodiversity loss, and emerging health threats. In response, the One Health framework has gained attention as an integrative approach encompassing human, animal, and environmental health. In a symposium at APPW2025, experts in Exposome science and Digital Transformation discussed how interdisciplinary integration can advance predictive and preventive medicine. This review summarizes five key topics: Exposome as a determinant of disease risk, epigenetic mechanisms encoding environmental memory, environmental programming of brown adipose tissue, adaptive prioritization of environmental signals, and simulation-based drug repurposing. Collectively, these studies highlight a paradigm shift from conventional linear exposure-disease models toward a systems-level understanding integrating cumulative exposures, biological memory, and predictive modeling. The convergence of Exposome science and Digital Transformation provides a foundation for advancing One Health into a predictive and actionable scientific framework.