Biology subjects

Nestel, S.

Publications and source records attributed to Nestel, S..

3 recordsLinked to original sources

bioRxiv2024

Developmental transcriptomics in Pristionchus reveals the logic of a plasticity gene regulatory network

Developmental plasticity enables the production of alternative phenotypes in response to different environmental conditions. While significant advances in understanding the ecological and evolutionary implications of plasticity have been made, understanding its genetic basis has lagged. However, a decade of genetic screens in the model nematode Pristionchus pacificus has culminated in 30 genes which affect mouth-form plasticity. We also recently reported the critical window of environmental sensitivity, and therefore have clear expectations for when differential gene expression should matter. Here, we collated previous data into a gene-regulatory network (GRN), and performed developmental transcriptomics across different environmental conditions, genetic backgrounds, and mouth-form mutants to assess the regulatory logic of plasticity. We found that only two genes in the GRN (eud-1 and seud-1/sult-1) are sensitive to the environment during the critical window. Interestingly, the time points of their sensitivity differ, suggesting that they act as sequential checkpoints. We also observed temporal constraint upon the transcriptional effects of mutating the GRN and revealed unexpected feedback between mouth-form genes. Surprisingly, expression of seud-1/sult-1, but not eud-1, correlated with mouth form biases across different strains and species. Finally, a comprehensive analysis of all samples identified metabolism as a shared pathway for regulating mouth-form plasticity. These data are presented in a Shiny app to facilitate gene-expression comparisons across development in up to 14 different conditions. Collectively, our results suggest that mouth-form plasticity evolved a constrained, two-tiered logic to integrate environmental information leading up to the final developmental decision.

genetics↗

bioRxiv2023

Regulation of hippocampal mossy fiber-CA3 synapse function by a Bcl11b/C1ql2/Nrxn3(25b+) pathway

The transcription factor Bcl11b has been linked to neurodevelopmental and neuropsychiatric disorders associated with synaptic dysfunction. Bcl11b is highly expressed in dentate gyrus granule neurons and is required for the structural and functional integrity of mossy fiber-CA3 synapses. The underlying molecular mechanisms, however, remained unclear. We show that the synaptic organizer molecule C1ql2 is a direct functional target of Bcl11b that regulates synaptic vesicle recruitment and long-term potentiation at mossy fiber-CA3 synapses in vivo and in vitro. Furthermore, we demonstrate C1ql2 to exert its functions through direct interaction with a specific splice variant of neurexin-3, Nrxn3(25b+). Interruption of C1ql2-Nrxn3(25b+) interaction by expression of a non-binding C1ql2 mutant or by deletion of Nrxn3 in the dentate gyrus granule neurons recapitulates major parts of the Bcl11b as well as C1ql2 mutant phenotype. Together, this study identifies a novel C1ql2-Nrxn3(25b+)-dependent signaling pathway through which Bcl11b controls mossy fiber-CA3 synapse function. Thus, our findings contribute to the mechanistic understanding of neurodevelopmental disorders accompanied by synaptic dysfunction.

neuroscience↗

bioRxiv2022

LRBA balances antigen presentation and T-cell responses by facilitating autophagy through the binding to PIK3R4 and FYCO1

Reduced autophagy is associated with the aberrant humoral response observed in lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency; however, the exact molecular mechanism and its impact on T-cell responses remain unknown. We identified two novel LRBA interactors, phosphoinositide 3-kinase regulatory subunit 4 (PIK3R4) and FYVE And Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). Both proteins play essential roles in different stages of autophagy. PIK3R4 facilitates the production of phosphatidylinositol-3 phosphate (PI(3)P) required for autophagosome formation and autophagosome-lysosome fusion, whereas FYCO1 allows autophagosome movement. LRBA-KO cells showed an impaired PI(3)P production, a delayed autophagosome-lysosome fusion, an accumulation of enlarged autophagosomes, and an atypical lysosomal positioning. These abnormalities led to decreased cargo material degradation and prolonged antigen presentation to T-cells via autophagy, resulting in increased production of proinflammatory cytokines, as autophagy is a major intracellular degradation system for major histocompatibility class II complex (MHCII) loading. Aberrant autophagosome formation, cargo degradation and antigen presentation were rescued by ectopic expression of WT-LRBA. In summary, we identified a novel function of LRBA that is crucial for T-cell-driven response through the interaction with two proteins of the autophagy machinery. These observations may contribute to the exacerbated T-cell dysregulation observed in LRBA-deficient patients.

immunology↗