Biology subjects

Umemori, H.

Publications and source records attributed to Umemori, H..

5 recordsLinked to original sources

bioRxiv2026

The Onset of Breathing at Birth Switches Off Regenerative Capacity

Many mammalian tissues, including the central nervous system (CNS), lose regenerative capacity in adulthood, but when and how this transition is initiated remains unclear. By monitoring mTOR activity, an evolutionarily conserved readout of cellular growth and intrinsic regenerative potential, we found that mTOR signaling declines within minutes after birth in murine CNS neurons and in other organs such as the heart and skeletal muscles. Focusing on retinal ganglion cells (RGCs), we show that this abrupt decline is driven primarily by CO2 exhalation following the onset of breathing after birth. Using real-time in vivo imaging of RGCs during the earliest postnatal period, we further discover that breathing-induced CO2 exhalation rapidly causes intracellular alkalinization, activates an AMPK-family kinase, SNF-related kinase (SNRK), which in turn suppresses mTOR signaling. Importantly, this process remains reversible in adulthood: CO2 inhalation or Snrk deletion restores mTOR activity in RGCs and enables robust regeneration of their axons after injury. Similar CO2 inhalation-induced mTOR reactivation occurs across multiple cell types and organs, suggesting a general mechanism by which breathing-associated CO2/pH signaling shapes the regenerative capacity across life and pointing to a potential CO2-based strategy for promoting tissue regeneration.

neuroscience↗

bioRxiv2025

δ2-Protocadherins organize parallel indirect basal ganglia circuits

The basal ganglia (BG) contain multiple parallel neural circuits, each of which may control different behaviors. However, how the distinct parallel BG circuits are molecularly organized is not known. Here we show that two {delta}2-protocadherins (PCDHs), PCDH17 and PCDH10, which are homophilic cell-adhesion molecules, establish and define two distinct indirect BG circuits that regulate different behaviors. PCDH17 and PCDH10 are expressed in a complementary expression pattern in the BG, anatomically defining two parallel indirect BG connections. Indirect pathway-specific Pcdh17 and Pcdh10 conditional knockout (cKO) mice show impaired establishment of the indirect BG circuits in a region-preferential manner. Finally, the Pcdh17-cKO mice show defects in task learning, while the Pcdh10-cKO mice show defects in motor/sensory habituation. These results identify PCDH17 and PCDH10 as the molecular organizers for two distinct indirect BG circuits regulating different behaviors and reveal the molecular mechanisms for organizing parallel BG circuits. TeaserDistinct protocadherins organize parallel indirect basal ganglia circuits that regulate task learning or sensorimotor habituation

neuroscience↗

bioRxiv2025

Hyperthermic Seizure Susceptibility and Focal Decreases in Parvalbumin-Expressing Cortical Interneurons in a Mouse Model of PCDH19-Clustering Epilepsy

ObjectiveProtocadherin-19 (PCDH19)-clustering epilepsy (PCE) is a severe genetic epilepsy that manifests with early-onset cluster seizures often triggered by fever, intellectual disability, autistic features, and later neuropsychiatric risk. PCDH19 is an X-linked gene critical for brain development. PCE predominantly affects females and rare mosaic males, but not hemizygous males, likely due to cellular mosaicism arising from random X-inactivation and resultant segregation of wild-type and mutant neurons (so-called cellular interference) during development. We generated a novel PCE mouse model and explored neuronal segregation, seizure susceptibility and cortical interneuron distributions. MethodsFemale Pcdh19+/- mice were crossed with X-GFP males to visualize random X-inactivation patterns. Seizure susceptibility was assessed in juvenile mice using hyperthermia and flurothyl exposure. Behavioral testing evaluated cognitive domains. Interneuron distribution in hippocampus and cortex was examined histologically by immunolabeling and crosses with parvalbumin reporter mice. ResultsJuvenile Pcdh19+/- females lacked spontaneous seizures but displayed lower seizure thresholds and more severe seizures during hyperthermia. Seizure susceptibility did not differ from controls after flurothyl exposure. Pcdh19+/- females also exhibited segregation of GFP+ cells in the cortex, hippocampal CA1 region and medial ganglionic eminence, with a marked reduction of parvalbumin-positive interneurons in the CA1 hippocampal region. Although parvalbumin interneuron density was unchanged in the Pcdh19+/- female cortex overall, localized decreases arose in GFP- (Pcdh19 knockout) cortical stripes. InterpretationJuvenile PCE mice exhibit seizure susceptibility to hyperthermia and disrupted the distribution of parvalbumin-expressing interneurons in the hippocampus and cortex. These findings suggest focal parvalbumin interneuron alterations may contribute to PCE pathophysiology.

neuroscience↗

bioRxiv2025

Molecular basis for shifted receptor recognition by an encephalitic arbovirus

After decades of inactivity throughout the Americas, western equine encephalitis virus (WEEV) recently re-emerged in South America, causing a large-scale outbreak in humans and horses. WEEV binds protocadherin 10 (PCDH10) as a receptor; however, nonpathogenic strains no longer bind human or equine PCDH10 but retain the ability to bind avian receptors. Highly virulent WEEV strains can also bind the very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) as alternative receptors. Here, by determining cryo-electron microscopy structures of WEEV strains isolated from 1941-2005 bound to mammalian receptors, we identify polymorphisms in the WEEV spike protein that explain shifts in receptor dependencies and that can allow nonpathogenic strains to infect primary cortical neurons. We predict the receptor dependencies of additional strains and of a related North American alphavirus. Our findings have implications for outbreak preparedness and enhance understanding of arbovirus neurovirulence through virus receptor binding patterns.

microbiology↗

bioRxiv2020

A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding

Developmental synaptic remodeling is important for the formation of precise neural circuitry and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes remains elusive. Adhesion G protein-coupled receptor ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: in neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS+ pre-synaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.

neuroscience↗