Subcommissural organ (SCO) contributes to brain development via SCO-secreted peptides
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ABSTRACT: To explore the role of SCO and its functional mechanism, we performed RNAseq between SCO and hippocampus at different stage to identify the expression of some unique genes and possible pathway related to the function of SCO. We cofirmed the role of SCO in neuronal development and identified three SCO-derived peptides which can contributed to neurite development and neuronal survival .
Project description:To explore the mechanism of SCO-derived peptides, we performed RNAseq in cultured neurons added with SCO peptide and control neurons which added with DPBS to identify the expression of some unique genes and possible pathway related to the function of SCO derived peptides. We cofirmed the role of SCO derived peptide which contribute in neuronal development,especially projection developent and cell survival. development and neuronal survival .
Project description:The subcommissural organ (SCO) is an ancient and evolutionarily conserved gland in the brain located at the entrance of the aqueduct of Sylvius. It exists in species as distantly related as amphioxus and humans, but the function of the SCO is still mysterious. Comparison of transcriptomes between SCO and non-SCO brain regions revealed three unique genes, namely Sspo, Car3, and Spdef, that are highly enriched in the SCO. We generated the corresponding gene knock-in mouse strains utilizing the Cre/lox recombinase system for specific expression in SCO cells. Genetic ablation of SCO cells at embryonic stages with these strains revealed that SCO excision resulted in severe hydrocephalus and developmental defects in the brain. Abnormalities were also observed for neuronal migration and axon and dendrite development in the cerebral cortex. Taking advantage of non-targeted peptidomic analysis, we identified three SCO-derived peptides, namely thymosin beta 4 (Tβ4), thymosin beta 10 (Tβ10), and NP24. We found that these SCO peptides contributed to neurite development and neuronal survival in vitro. Indeed, application of a cocktail containing Tβ4, Tβ10 and NP24 to SCO-ablated brain ventricles substantially rescued their developmental defects. Our results demonstrate that SCO-derived peptides play critical roles in neuronal development.
Project description:To explore the role of SCO and its functional mechanism, we measure the SCO-derived peptide in CSF from C57B/6 mice and SCO-ablated mice.
Project description:The novel neuroproteasome is localized to the neuronal plasma membrane to degrade intracellular proteins into peptides that are released to the extracellular space. Selective inhibition of this neuronal membrane proteasome (NMP) complex ceased the release of peptides and rapidly attenuated neuronal transmission. Based on these findings, we hypothesize that these neuron-specific peptides mediate a novel form of communication through unique peptide-receptor interactions to promote intracellular signaling cascades relevant to neuronal development and function. Our work indicates that NMP peptides can rapidly induce N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx from dendrites to the soma, leading to rapid and sustained phosphorylation of the well-defined activity-dependent transcription factor cAMP response element-binding protein (CREB). We also determined that the gene expression program drastically changes upon NMP peptide treatment of neurons with an increase in expression of immediate early genes (e.g., Fos, Npas4, Egr4) known to have critical neuroregulatory roles. These data support our current thinking that NMP peptides are endogenous and selective activators of synaptic NMDA receptors and are critical for promoting activity-dependent gene expression. This pathway is orthogonal to the classic neurotransmitters previously described to activate NMDARs and points to NMP and its resulting peptides as key contributors to the development and function of the nervous system. However, the unique peptide sequences leading to neuronal activation are still poorly understood. Here, we show that the NMP peptides have tremendous sequence diversity through an unbiased peptidomic approach, and the current ongoing effort is to identify unique active peptide sequences with distinct receptor specificity. Elucidating the mechanism of the NMP and its active peptide products is crucial to understanding the role of this novel signaling process in the nervous system.
Project description:The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.
Project description:To investigate the mode of action of a novel class of antifungal synthtic acrylamide peptides, the pathogenic yeast, Candida albicans, was exposed to sublethal doses of peptides with different structures. The experiments include the most effective structure, LH, peptides with no antifungal effects (HEAm) and intermediates as well as controls.
Project description:The central nervous system (CNS), despite the presence of strategically positioned anatomical barriers designed to protect it, is not entirely isolated from the immune system1,2. In fact, it remains physically connected to and can be influenced by the peripheral immune system. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding conundrum. In searching for molecular cues that derive from the CNS and allow its direct communication with the immune system, we discovered a repertoire of CNS-derived endogenous regulatory self-peptides presented on major histocompatibility complex (MHC) II molecules at the CNS borders. During homeostasis, a preponderance of these regulatory self-peptides were found to be bound to MHC II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. With neuroinflammatory disease, however, the presentation of regulatory self-peptides diminished. Upon boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells could be expanded, controlling CNS autoimmunity in a CTLA-4 and TGF dependent manner. This unexpected discovery of CNS-derived autoimmune self-peptides may be the molecular key adapting the CNS to maintain continuous dialogue with the immune system while balancing overt autoreactivity. This sheds new light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases.