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Nomura, J.

Publications and source records attributed to Nomura, J..

3 recordsLinked to original sources

Endocytosis-mediated vitellogenin absorption and lipid metabolism in the hindgut-derived pseudoplacenta of the viviparous teleost Xenotoca eiseni

Certain viviparous animals possess mechanisms for mother-to-embryo nutrient transport during gestation. Xenotoca eiseni is one such viviparous teleost species in which the mother supplies proteins and other components to the offspring developing in the ovary. The embryo possesses trophotenia, a hindgut-derived pseudoplacenta to receive the maternal supplement. However, the molecular mechanisms underlying viviparous non-mammalian animals remain elusive. We conducted this study to investigate the mechanism for nutrient absorption and degradation in trophoenia of X. eiseni. The tracer assay indicated that a lipid transfer protein, vitellogenin (Vtg), was absorbed into the epithelial layer cells of trophotaenia. Vtg uptake was significantly suppressed by Pitstop-2, an inhibitor of clathrin-mediated endocytosis. Gene expression analysis indicated that the genes involved in endocytosis-mediated lipolysis and lysosomal cholesterol transport were expressed in trophotaenia. In contrast, plasma membrane transporters expressed in the intestinal tract were not functional in trophotaenia. Our results suggested that endocytosis-mediated lysosomal lipolysis is one of the mechanisms underlying maternal component metabolism. Thus, our study demonstrated how viviparous teleost species have acquired a unique developmental system that is based on the hindgut-derived pseudoplacenta.

zoology↗

Autism in a dish: ES cell models of autism with copy number variations reveal cell-type-specific vulnerability

Human genetics has identified numerous single nucleotide variations (SNVs) and copy number variations (CNVs) associated with autism spectrum disorders (ASD) and other psychiatric disorders. However, the lack of standardized biological resources impedes understanding of the common pathophysiology of ASD. Here, using next-generation chromosome engineering based on the CRISPR/Cas9 system, we established a biological resource including 65 genetically modified mouse embryonic stem cell (mESC) lines as genetic models of human SNVs and CNVs. To illustrate cell-type and CNV specific molecular features of ASD, we performed single-cell RNA sequencing (37,397 cells in total), morphological, and physiological analyses using 12 representative cell lines with CNVs highly associated with ASD. These results uncover gene ontology (GO) terms, canonical pathways, upstream regulators, and related neuropsychiatric disorders in a cell-type and CNV specific manner.

neuroscience↗

Reciprocal differentiation via GABAergic components and ASD-related phenotypes in hES with 1q21.1 CNV

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup), are associated with autism spectrum disorder, epilepsy and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes--e.g., microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms are still elusive. We generate isogenic human ES (hES) cell lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and 3-D cortical organoids. Our study recapitulates opposite organoid size and shows dosage-dependent differentiation changes i.e., more mature and GABAergic components in 1q del and more proliferative state in 1q dup. In contrast, both CNVs show hyperexcitability and altered expressions of glutamate system as common features. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic model of hES CNVs and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.

genomics↗