Congenital anomalies of the kidney and urinary tract (CAKUT) are the third most common congenital anomaly and a significant public health concern. It is the predominant cause of chronic renal disease in pediatric populations and the principal reason for kidney replacement therapy in individuals under 20, as well as the fourth leading cause in adults. Five candidate genes, including EDA2R, PCDH9, and TRAF7 were identified as potential contributors to CAKUT. These genes had not been previously prioritized in CAKUT research, and our prior studies have demonstrated that the proteins encoded by these candidate genes display dysregulated expression across various CAKUT subgroups. Our research examined the expression patterns of EDA2R, PCDH9, and TRAF7 in yotari (Dab1^−/−) mice at two embryonic stages (E13.5 and E15.5) and two postnatal stages (P4 and P14) to ascertain the potential correlation between Reelin–Dab1 signaling, previously linked to CAKUT phenotypes, and the aforementioned proteins through molecular and morphological analyses. All three observed proteins exhibited the highest area percentage at E13.5, with a trend of decline into postnatal stages, during which specific changes in protein expression were noted between the cortex and medulla of yotari mice compared to wild-type mice. For TRAF7, a statistically significant difference in area percentage at E13.5 was observed, indicating a link with Reelin–Dab1 signaling and a potentially critical role in the pathophysiology of CAKUT, also marked by our prior study.

Human genome studies have suggested that strawberry notch homologue 1 (SBNO1) is crucial for normal brain development, with mutations potentially contributing to neurodevelopmental disorders. In a previous study, we observed significant developmental abnormalities in the neocortex of Sbno1 as early as one week after birth. In the present study, we conducted an extensive analysis of Sbno1 postnatal expression in the brain of C57BL/6 mice using a newly developed in-house polyclonal antibody against Sbno1. We found that Sbno1 is expressed in all neurons, with certain neuronal populations exhibiting distinct dynamic changes (both temporal and spatial) in expression level. These findings suggest that the neuronal expression of Sbno1 is developmentally regulated after birth. They also indicate that while Sbno1 may play a general role across all neurons, it may also serve more specialized functions in certain neuronal types and/or for certain cellular activities related to particular neuronal pathways.

Neurons are subjected to various stresses, including high metabolic demand, physiological activity, and transcriptional regulation, to which their genomic DNA are vulnerable. Genome stability of neurons is essential for proper physiological brain function. Failure in accurate genomic DNA repair can result in abnormal neuronal functions or cell death. Genomic instability has been implicated in increased risks of neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms underlying neuronal genome stability remain poorly understood. Mutations in the Strawberry Notch Homolog 1 (SBNO1) have been suggested to contribute to these disorders. Here, we investigated the molecular mechanisms underlying histological abnormalities observed in the cortex of Sbno1 knockout (KO) mice. Comprehensive gene expression analysis revealed that Sbno1 KO affects the expression of genes related to cell survival, consistent with the increased apoptosis observed in Sbno1 KO cortices. Among the genes downregulated in Sbno1 KO, we focused on Yeats4. Overexpression of Yeats4 rescued the accumulation of genomic DNA damage and cell death caused by Sbno1 deletion. These findings suggest that Sbno1 is critical in safeguarding the neuronal genome, at least in part, via regulating Yeats4 expression.

Stem cell (SC) aging is implicated in tissue dysfunction and organismal aging. However, the molecular basis of aging shared across diverse adult SC types remains unclear. Here, we identify the transcription factor Lef1 , the splicing regulator Srsf3 , and a subset of DNA damage response microRNAs (DDR-miRs) as a common molecular axis underlying SC aging. Lef1 was the most consistently downregulated transcription factor during aging, common to mesenchymal stem/stromal cells (MSCs) and hematopoietic stem/progenitor cells (HSCs), and this reduction was also observed in other tissue SC types in both mice and humans based on reanalysis of public RNA-seq datasets. In young MSCs, Lef1 knockdown reproduced a miRNA expression profile similar to that of aged MSCs. Using in vitro reporter assays for mirtron biogenesis, a non-canonical miRNA biogenesis process, we identified age-associated cytoplasmic translocation and functional attenuation of Srsf3 as the causal molecular alteration responsible for impaired miRNA biogenesis under reduced Wnt signaling. Consistent with these in vitro findings, DDR capacity was reduced in aged SCs in vivo. Stem cell-specific Lef1 deletion in either intestinal or epidermal stem cells in young mice induced premature DDR impairment and elicited inflammatory and senescence-like phenotypes in remote organs, including the brain, skin, and kidney. These findings define the decay of the Lef1 - Srsf3 -miRNA axis as a core molecular alteration underlying SC aging and reveal that local SC aging may contribute to organismal aging.

Human genome studies have suggested that strawberry notch homologue 1 (SBNO1) is crucial for normal brain development, with mutations potentially contributing to neurodevelopmental disorders. In a previous study, we observed significant developmental abnormalities in the neocortex of Sbno1 as early as one week after birth. In the present study, we conducted an extensive analysis of Sbno1 postnatal expression in the brain of C57BL/6 mice using a newly developed in-house polyclonal antibody against Sbno1. We found that Sbno1 is expressed in all neurons, with certain neuronal populations exhibiting distinct dynamic changes (both temporal and spatial) in expression level. These findings suggest that the neuronal expression of Sbno1 is developmentally regulated after birth. They also indicate that while Sbno1 may play a general role across all neurons, it may also serve more specialized functions in certain neuronal types and/or for certain cellular activities related to particular neuronal pathways.

Adult tissue stem cells (SCs) play an important role in tissue homeostasis and regeneration in multicellular organisms. With aging, these cells d | POSTER