Biology subjects

Li, M.-Y.

Publications and source records attributed to Li, M.-Y..

4 recordsLinked to original sources

bioRxiv2023

Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway

Abnormalities in crosstalk between the thalamus and the cerebral cortex are thought to lead to severe neuropsychiatric disorders, such as epilepsy and psychotic disorders. Pathogenic variants in the CACNA1G gene, which encodes the 1G subunit of the thalamus-enriched T-type voltage-gated calcium channel CaV3.1, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit level consequences of these genetic variants in humans remain unknown. Here, we developed an in vitro human assembloid model of the thalamocortical pathway to systematically dissect the contribution of genetic variants in T-type calcium channels. We discovered that a CACNA1G variant (M1531V) associated with seizures led to changes in T-type currents in human thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in thalamo-cortical assembloids. In contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant thalamic axonal projections. Taken together, these results illustrate the utility of organoid and assembloid systems for interrogating human genetic disease risk variants at both cellular and circuit level.

neuroscience↗

bioRxiv2022

Fibroblast activation during decidualization: Embryo-derived TNFα induction of PGI2-PPARδ-ACTIVIN A pathway through luminal epithelium

ObjectivesHuman endometrium undergoes cyclical shedding and bleeding, scar-free repair and regeneration in subsequent cycles. Fibroblast activation has been shown to play a key role during normal tissue repair and scar formation. Abnormal fibroblast activation leads to fibrosis. Fibrosis is the main cause of intrauterine adhesion, uterine scaring, and thin endometrium. Endometrial decidualization is a critical step during early pregnancy. There are 75% of pregnancy failures pointed to decidualization defects. Because fibroblast activation and decidualization share similar markers, we assumed that fibroblast activation should be involved in decidualization. Materials and MethodsBoth pregnant and pseudopregnant ICR mice were used in this study. Immunofluorescence and immunohistochemistry were applied to examine fibroblast activation-related markers in mouse uteri. Western blotting was used to identify the impact on decidualization. Western blot and RT were used to show how arachidonic acid and its downstream product prostaglandin activate fibroblasts. Additionally, embryo-derived TNF was shown to stimulate the secretion of arachidonic acid by immunofluorescence, western blot, and ELASA. The aborted decidual tissues with fetal trisomy 16 were compared with control tissues. GraphPad Prism5.0 Students t test was used to compare differences between control and treatment groups ResultsFibroblast activation-related markers are obviously detected in pregnant decidua and under in vitro decidualization. ACTIVIN A secreted under fibroblast activation promotes in vitro decidualization. We showed that arachidonic acid released from uterine luminal epithelium can induce fibroblast activation and decidualization through PGI2 and its nuclear receptor PPAR-{delta}. Based on the significant difference of fibroblast activation-related markers between pregnant and pseudopregnant mice, we found that embryo-derived TNF promotes cPLA2 phosphorylation and arachidonic acid release from luminal epithelium. Fibroblast activation is also detected under human in vitro decidualization. Similar arachidonic acid-PGI2-PPAR{delta}-ACTIVIN A pathway is conserved in human endometrium. Compared to controls, fibroblast activation is obviously compromised in human decidual tissues with fetal trisomy 16. ConclusionsEmbryo-derived TNF promotes cPLA2 phosphorylation and arachidonic acid release from luminal epithelium to induce fibroblast activation and decidualization. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=144 HEIGHT=200 SRC="FIGDIR/small/509003v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@97b4edorg.highwire.dtl.DTLVardef@1e758d6org.highwire.dtl.DTLVardef@1797acaorg.highwire.dtl.DTLVardef@6c8b82_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2022

Incorporating uniparental markers and demographic information in kinship analysis

Knowledge of kinship relations between members of wild populations is of great importance in ecological and conservation genetic studies. The bi-parentally inherited autosomal markers has been the Golden Standard in kinship analysis. However, analysis of kin relationship can be challenging in wild populations. The uni-parentally inherited markers and population demographic information can be helpful for identifying false-positive in kinship analysis. Here we showed how incorporating uniparental genetic and demographic information can improve the correct classification rate of kinship analyses by reanalyzing data of a recent study published in Science Advances. The application of next generation high-throughput sequencing to address fundamental ecological questions is of immense benefit to the field of molecular ecology, which could also generate uniparentally inherited organelle genomes together with nuclear data. We strongly recommended that uniparental genetic markers and demographic information be seriously considered in kinship analyses of wild populations.

ecology↗

bioRxiv2021

Dissecting the molecular basis of human interneuron migrationin forebrain assembloids from Timothy syndrome

Defects in interneuron migration during forebrain development can disrupt the assembly of cortical circuits and have been associated with neuropsychiatric disease. The molecular and cellular bases of such deficits have been particularly difficult to study in humans due to limited access to functional forebrain tissue from patients. We previously developed a human forebrain assembloid model of Timothy Syndrome (TS), caused by a gain-of-function mutation in CACNA1C which encodes the L-type calcium channel (LTCC) Cav1.2. By functionally integrating human induced pluripotent stem cell (hiPSC)-derived organoids resembling the dorsal and ventral forebrain from patients and control individuals, we uncovered that migration is disrupted in TS cortical interneurons. Here, we dissect the molecular underpinnings of this phenotype and report that acute pharmacological modulation of Cav1.2 can rescue the saltation length but not the saltation frequency of TS migrating interneurons. Furthermore, we find that the defect in saltation length in TS interneurons is associated with aberrant actomyosin function and is rescued by pharmacological modulation of MLC phosphorylation, whereas the saltation frequency phenotype in TS interneurons is driven by enhanced GABA sensitivity and can be restored by GABA receptor antagonism. Overall, these findings uncover multi-faceted roles of LTCC function in human cortical interneuron migration in the context of disease and suggest new strategies to restore interneuron migration deficits.

neuroscience↗