RESUMEN
Lipids are indispensable for energy storage, membrane structure and cell signalling. However, dynamic changes in various categories of endogenous lipids in mammalian early embryonic development have not been systematically characterized. Here we comprehensively investigated the dynamic lipid landscape during mouse and human early embryo development. Lipid signatures of different developmental stages are distinct, particularly for the phospholipid classes. We highlight that the high degree of phospholipid unsaturation is a conserved feature as embryos develop to the blastocyst stage. Moreover, we show that lipid desaturases such as SCD1 are required for in vitro blastocyst development and blastocyst implantation. One of the mechanisms is through the regulation of unsaturated fatty-acid-mediated fluidity of the plasma membrane and apical proteins and the establishment of apical-basal polarity during development of the eight-cell embryo to the blastocyst. Overall, our study provides an invaluable resource about the remodelling of the endogenous lipidome in mammalian preimplantation embryo development and mechanistic insights into the regulation of embryogenesis and implantation by lipid unsaturation.
Asunto(s)
Metabolismo de los Lípidos , Lipidómica , Embarazo , Humanos , Femenino , Ratones , Animales , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/fisiología , Blastocisto/metabolismo , Fosfolípidos/metabolismo , MamíferosRESUMEN
Nrg1 (Neuregulin 1) type III, a susceptible gene of schizophrenia, exhibits a critical role in the central nervous system and is essential at each stage of Schwann's cell development. Nrg1 type III comprises double-pass transmembrane domains, with the N-terminal and C-terminal localizing inside the cells. The N-terminal transmembrane helix partially overlaps with the cysteine-rich domain (CRD). In this study, Nrg1 type III constructs with different tags were transformed into cultured cells to verify whether CRD destroyed the transmembrane helix formation. We took advantage of immunofluorescent and immunoprecipitation assays on whole cells and analyzed the N-terminal distribution. Astonishingly, we found that a novel form of Nrg1 type III, about 10% of Nrg1 type III, omitted the N-terminal transmembrane helix, with the N-terminal positioning outside the membrane. The results indicated that the novel single-pass transmembrane status was a minor form of Nrg1 type III caused by N-terminal processing, while the major form was a double-pass transmembrane status.
Asunto(s)
Neurregulina-1 , Esquizofrenia , Humanos , Neurregulina-1/genética , Esquizofrenia/genéticaRESUMEN
Rapsyn, an intracellular scaffolding protein associated with the postsynaptic membranes in the neuromuscular junction (NMJ), is critical for nicotinic acetylcholine receptor clustering and maintenance. Therefore, Rapsyn is essential to the NMJ formation and maintenance, and Rapsyn mutant is one of the reasons causing the pathogenies of congenital myasthenic syndrome (CMS). In addition, there is little research on Rapsyn in the central nervous system (CNS). In this review, the role of Rapsyn in the NMJ formation and the mutation of Rapsyn leading to CMS will be reviewed separately and sequentially. Finally, the potential function of Rapsyn is prospected.
Asunto(s)
Síndromes Miasténicos Congénitos , Humanos , Síndromes Miasténicos Congénitos/genética , Receptores Colinérgicos/genética , Unión Neuromuscular/metabolismo , Proteínas Musculares/genéticaRESUMEN
BACKGROUND: Abnormal white matter is a common neurobiological change in bipolar disorder, and dysregulation of myelination in oligodendrocytes (OLs) is the cause. Transmembrane protein 108 (Tmem108), as a susceptible gene of bipolar disorder, is expressed higher in OL lineage cells than any other lineage cells in the central nervous system. Moreover, Tmem108 mutant mice exhibit mania-like behaviors, belonging to one of the signs of bipolar disorder. However, it is unknown whether Tmem108 regulates the myelination of the OLs. RESULTS: Tmem108 expression in the corpus callosum decreased with the development, and OL progenitor cell proliferation and OL myelination were enhanced in the mutant mice. Moreover, the mutant mice exhibited mania-like behavior after acute restraint stress and were susceptible to drug-induced epilepsy. CONCLUSIONS: Tmem108 inhibited OL progenitor cell proliferation and mitigated OL maturation in the corpus callosum, which may also provide a new role of Tmem108 involving bipolar disorder pathogenesis.
Asunto(s)
Cuerpo Calloso , Sustancia Blanca , Animales , Linaje de la Célula , Proliferación Celular , Manía , Ratones , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismoRESUMEN
Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems. Because of the challenges in disease-causing gene identification and mechanism elucidation, patients are often confronted with difficulty obtaining a precise diagnosis and treatment. Due to advances in sequencing and multiomics analysis approaches combined with patient-derived iPSC models and gene-editing platforms, substantial progress has been made in the diagnosis and treatment of rare and undiagnosed diseases. The aforementioned techniques also provide an operational basis for future precision medicine studies. In this review, we summarize recent progress in identifying disease-causing genes based on GWAS/WES/WGS-guided multiomics analysis approaches. In addition, we discuss recent advances in the elucidation of pathogenic mechanisms and treatment of diseases with state-of-the-art iPSC and organoid models, which are improved by cell maturation level and gene editing technology. The comprehensive strategies described above will generate a new paradigm of disease classification that will significantly promote the precision and efficiency of diagnosis and treatment for rare and undiagnosed diseases.
RESUMEN
Background: Schizophrenia (SCZ) is a severe psychiatric disease affected by genetic factors and environmental contributors, and premorbid abnormality of glucose metabolism is one of the SCZ characteristics supposed to contribute to the disease's pathological process. Transmembrane protein 108 (Tmem108) is a susceptible gene associated with multiple psychiatric diseases, including SCZ. Moreover, Tmem108 mutant mice exhibit SCZ-like behaviors in the measurement of sensorimotor gating. However, it is unknown whether Tmem108 regulates glucose metabolism homeostasis while it involves SCZ pathophysiological process. Results: In this research, we found that Tmem108 mutant mice exhibited glucose intolerance, insulin resistance, and disturbed metabolic homeostasis. Food and oxygen consumption decreased, and urine production increased, accompanied by weak fatigue resistance in the mutant mice. Simultaneously, the glucose metabolic pathway was enhanced, and lipid metabolism decreased in the mutant mice, consistent with the elevated respiratory exchange ratio (RER). Furthermore, metformin attenuated plasma glucose levels and improved sensorimotor gating in Tmem108 mutant mice. Conclusions: Hyperglycemia occurs more often in SCZ patients than in control, implying that these two diseases share common biological mechanisms, here we demonstrate that the Tmem108 mutant may represent such a comorbid mechanism.
Asunto(s)
Metabolismo de los Hidratos de Carbono/genética , Glucosa/metabolismo , Homeostasis/genética , Resistencia a la Insulina/genética , Esquizofrenia/genética , Proteínas de Transporte Vesicular/genética , Animales , Ingestión de Alimentos/genética , Intolerancia a la Glucosa/genética , Metabolismo de los Lípidos/genética , Ratones , Ratones Noqueados , Consumo de Oxígeno/genéticaRESUMEN
Toll-like receptor 9 (TLR9) is activated by bacterial DNA and induces the production of inflammatory cytokines. In this study, the darkbarbel catfish Pelteobagrus vachellii TLR9 cDNA was cloned and sequenced. The daily expression pattern of TLR9 mRNA was investigated in various tissues. Furthermore, its expression was analyzed following exposure to the pathogen Aeromonas hydrophila. The 4249 bp cDNA includes a 3201 bp open reading frame (ORF) encoding 1067 amino acids. The predicted amino acid sequence comprises a leucine-rich domain (LRD), a toll/interleukin-1 receptor (TIR), and a transmembrane domain. P. vachellii TLR9 showed 42-87% amino acid sequence identity with TLR9 sequences of Ictalurus punctatus, Rhincodon typus, and Miichthys miiuy. The P. vachellii TLR9 mRNA was highly expressed in intestines, head kidney, and spleen in an apparently healthy fish. Following pathogen challenge, TLR9 expression increased significantly (Pâ¯<â¯0.05) and peaked at 48â¯h post-exposure in the liver, at 24 in the head kidney, and at 12â¯h in the spleen. In addition, the pattern of TLR9 expression over a 24-h period showed a circadian rhythm in the head kidney, spleen, and intestine, with the acrophase at 20:34, 18:45, and 3:50, respectively. This result provided the basis for further study of the rhythm of innate immunity against bacteria in catfish.
Asunto(s)
Bagres/genética , Bagres/inmunología , Enfermedades de los Peces/inmunología , Regulación de la Expresión Génica/inmunología , Inmunidad Innata/genética , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/inmunología , Aeromonas hydrophila/fisiología , Secuencia de Aminoácidos , Animales , Proteínas de Peces/química , Proteínas de Peces/genética , Proteínas de Peces/inmunología , Perfilación de la Expresión Génica/veterinaria , Infecciones por Bacterias Gramnegativas/inmunología , Infecciones por Bacterias Gramnegativas/veterinaria , Filogenia , Alineación de Secuencia/veterinaria , Receptor Toll-Like 9/químicaRESUMEN
OBJECTIVE: To explore the feasibility of autologous burn eschar as the coverage of microskin grafting in the repair of excised severe burn wounds. METHODS: Twelve severe burn patients underwent massive escharectomy during 3 to 7 post burn days (PBD), and autologous eschar instead of alloskin was employed as the coverage of microskin. The integrity of grafted eschar and survival of microskin grafts were observed at 1 to 6 weeks after operation. The wound healing rate in grafted area was determined at 6 post operation week (POW), and the wound healing time was recorded. RESULTS: The autologous eschar in the grafted area were integral and attached tightly to the wound during the 1 to 2 POW and began to dry and detach from the burn wound with the microskin underneath growing and fusing at 3-4 POW. This process went on until the eschar was completely detached from the burn wound and the microskin fused in large areas, with some granulation wounds left at 5 and 6 POW. The wound healing rate at the 6 POW was (87 +/- 4)%. The average wound healing time of burn patients in this group was (56 +/- 8) days. CONCLUSION: Autologous eschar could be used as a substitute for the alloskin for microskin grafting in excised burn wounds.