LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

Libé-Philippot, Baptiste; Lejeune, Amélie; Wierda, Keimpe; Louros, Nikolaos; Erkol, Emir; Vlaeminck, Ine; Beckers, Sofie; Gaspariunaite, Vaiva; Bilheu, Angéline; Konstantoulea, Katerina; Nyitrai, Hajnalka; De Vleeschouwer, Matthias; Vennekens, Kristel M.; Vidal, Niels; Bird, Thomas W.; Soto, Daniela C.; Jaspers, Tom; Dewilde, Maarten; Dennis, Megan Y.; Rousseau, Frederic; Comoletti, Davide; Schymkowitz, Joost; Theys, Tom; de Wit, Joris; Vanderhaeghen, Pierre

doi:10.1016/j.cell.2023.11.028

Cited by 16 publications

(2 citation statements)

References 109 publications

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“…In comparison, LRRC37B expression changes were significantly affected in three out of the four conditions by RNA-seq analysis, and this effect on LRRC37B expression changes was also confirmed by RT-qPCR for both VILMIR KD lines in the 10 ng/mL IFN-β treatment (Figure S1D-E). Since the observed magnitude of VILMIR KD effect on LRRC37B expression change was relatively small (average -ΔΔCt difference of -0.27 or a decrease of 0.83-fold by RT-qPCR) and LRRC37B was reported as a membrane receptor in neurons (58), the potential effect of VILMIR KD on LRRC37B needs to be further investigated.…”

Section: Resultsmentioning

confidence: 99%

Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response

John,

Huntress,

Smith

et al. 2024

Preprint

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Long noncoding RNAs (lncRNAs) are a newer class of noncoding transcripts identified as key regulators of biological processes. Here we aimed to identify novel lncRNA targets that play critical roles in major human respiratory viral infections by systematically mining large-scale transcriptomic datasets. Using bulk RNA-sequencing (RNA-seq) analysis, we identified a previously uncharacterized lncRNA, named virus inducible lncRNA modulator of interferon response (VILMIR), that was consistently upregulated afterin vitroinfluenza infection across multiple human epithelial cell lines and influenza A virus subtypes.VILMIRwas also upregulated after SARS-CoV-2 and RSV infectionsin vitro. We experimentally confirmed the response ofVILMIRto influenza infection and interferon-beta (IFN-β) treatment in the A549 human epithelial cell line and found the expression ofVILMIRwas robustly induced by IFN-β treatment in a dose and time-specific manner. Single cell RNA-seq analysis of bronchoalveolar lavage fluid (BALF) samples from COVID-19 patients uncovered thatVILMIRwas upregulated across various cell types including at least five immune cells. The upregulation ofVILMIRin immune cells was further confirmed in the human T cell and monocyte cell lines, SUP-T1 and THP-1, after IFN-β treatment. Finally, we found that knockdown ofVILMIRexpression reduced the magnitude of host transcriptional responses to IFN-β treatment in A549 cells. Together, our results show thatVILMIRis a novel interferon-stimulated gene (ISG) that regulates the host interferon response and may be a potential therapeutic target for human respiratory viral infections upon further mechanistic investigation.

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Section: Resultsmentioning

confidence: 99%

Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response

John,

Huntress,

Smith

et al. 2024

Preprint

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“…To identify potential candidate genes acting as human-specific modifiers of microglia morphological and/or functional maturation, we examined human-specific gene duplications. We and others recently demonstrated that human-specific gene duplications represent a potent source of human-specific genomic modifiers of neuronal development and connectivity, ultimately impacting cortical circuit function 30,43–47 . Interestingly, module 160 contains SLIT-ROBO Rho GTPase activating protein 2 ( Srgap2 in mammals, named SRGAP2A in human ) , a gene that has undergone two main partial duplications leading to the emergence of the human-specific paralogs Srgap2b and Srgap2c approximately 3.5-2.4 million years ago (mya) 44,48 .…”

Section: Resultsmentioning

confidence: 99%

Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation

Diaz-Salazar,

Krzisch,

Yoo

et al. 2024

Preprint

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SUMMARYMicroglia play key roles in shaping synaptic connectivity during neural circuits development. Whether microglia display human-specific features of structural and functional maturation is currently unknown. We show that the ancestral geneSRGAP2Aand its human-specific (HS) paralogsSRGAP2B/Care not only expressed in cortical neurons but are the only HS gene duplications expressed in human microglia. Here, using combination of xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that (1) HS SRGAP2B/C are necessary and sufficient to induce neotenic features of microglia structural and functional maturation in a cell-autonomous manner, and (2) induction of SRGAP2-dependent neotenic features of microglia maturation non-cell autonomously impacts synaptic development in cortical pyramidal neurons. Our results reveal that, during human brain evolution, human-specific genes SRGAP2B/C coordinated the emergence of neotenic features of synaptic development by acting as genetic modifiers of both neurons and microglia.

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Deciphering the role of structural variation in human evolution: a functional perspective

Karageorgiou,

Gokcumen,

Dennis

2024

Current Opinion in Genetics & Development

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LRRC37B is a human modifier of voltage-gated sodium channels and axon excitability in cortical neurons

Cited by 16 publications

References 109 publications

Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response

Human long noncoding RNA,VILMIR,is induced by major respiratory viral infections and modulates the host interferon response

Human-specific paralogs of SRGAP2 induce neotenic features of microglia structural and functional maturation

Deciphering the role of structural variation in human evolution: a functional perspective

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