Three-tier regulation of cell number plasticity by neurotrophins and Tolls in <i>Drosophila</i>

Földi, István; Anthoney, Niki; Harrison, Neale; Gangloff, Monique; Verstak, Brett; Nallasivan, Mohanakarthik Ponnadai; AlAhmed, Samaher; Zhu, Bangfu; Phizacklea, Mark; Losada‐Pérez, María; Moreira, Marta; Hidalgo, Alicia

doi:10.1083/jcb.201607098

Cited by 37 publications

(159 citation statements)

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“…Toll-6 is proposed to have neurotrophic activity based on analysis of Toll-6 nulls (Foldi et al, 2017;McIlroy et al, 2013). Yet, the specific cellular requirements for Toll-6 function were not investigated.…”

Section: Cortex Glial Toll-6 Signaling Limits Apoptotic Debris In Thementioning

confidence: 99%

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

et al. 2019

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Graphical Abstract Highlights d Dying neurons signal to phagocytic glia via a Toll receptor pathway during development d Dying neurons activate Furin-dependent processing of the Toll-6 ligand, Spz5 d Cortex glia sense cleaved Spz5 via Toll-6-dSARM signaling d Toll-6 signaling drives transcriptional upregulation of the Draper engulfment receptor SUMMARYGlia continuously survey neuronal health during development, providing trophic support to healthy neurons while rapidly engulfing dying ones. These diametrically opposed functions necessitate a foolproof mechanism enabling glia to unambiguously identify those neurons to support versus those to engulf. To ensure specificity, glia are proposed to interact with dying neurons via a series of carefully choreographed steps. However, these crucial interactions are largely obscure. Here we show that dying neurons and glia communicate via Toll-receptor-regulated innate immune signaling. Neuronal apoptosis drives processing and activation of the Toll-6 ligand, Sp € atzle5. This cue activates a dSARM-mediated Toll-6 transcriptional pathway in glia, which controls the expression of the Draper engulfment receptor. Pathway loss drives earlyonset neurodegeneration, underscoring its functional importance. Our results identify an upstream priming signal that prepares glia for phagocytosis. Thus, a core innate immune pathway plays an unprecedented role setting the valence of neuron-glia interactions during development.Developmental Cell 48, 506-522, February 25, 2019 507 on the manuscript. We also appreciate helpful discussions with members of the Broihier and Landreth labs.

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Section: Cortex Glial Toll-6 Signaling Limits Apoptotic Debris In Thementioning

confidence: 99%

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

et al. 2019

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“…Our data suggest that Kek-6 and Toll-6 influence synaptic structure via alternative, independent pathways. Toll-6 functions in neurons via a canonical pathway to regulate NFκB and JNK [36]; Toll-8 and Toll-6 regulate NMJ plasticity also via an alternative dFOXO pathway[37,43]; and we show that Kek-6 functions via CaMKII and VAP33A to regulate synaptic structure independently of Toll-6 (Fig. 12B).…”

Section: Discussionmentioning

confidence: 73%

“…2A). Stimulation with DNT2-CK in pDONR transfected controls induced dros-luc , as S2 cells express multiple Toll receptors [36,38] (Fig. 2A).…”

Section: Resultsmentioning

confidence: 99%

“…To test if DNT2 could function retrogradely, we generated a tagged form of full-length DNT2 with GFP at the C-terminus, and over-expressed DNT2-FL-GFP in the muscle with MhcGAL4 . DNT2-FL-GFP would result in secretion of mature DNT2-CK-GFP [36], although not all protein might get cleaved and secreted. Over-expression of DNT2-FL-GFP in muscle resulted in the localization of GFP pre-synaptically in boutons, surrounded by the post-synaptic marker Dlg (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The prime candidates for Kek ligands are the Drosophila neurotrophins (DNTs). DNT1 ( Drosophila neurotrophin 1 also known as Spz2), DNT2 (also known as Spz5) and Spz bear the distinctive and evolutionarily conserved neurotrophin cystine-knot domain of the mammalian neurotrophins [28-36], and they have conserved CNS functions regulating neuronal survival, connectivity and synaptogenesis [35-39]. Spz, DNT2 and DNT1 are known ligands for Toll-1, Toll-6 and Toll-7 receptors of the Toll and Toll-Like Receptor (TLR) superfamily [38,40].…”

Section: Introductionmentioning

confidence: 99%

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KEK-6: A TRUNCATED-TRK-LIKE RECEPTOR FORDROSOPHILANEUROTROPHIN 2 REGULATES STRUCTURAL SYNAPTIC PLASTICITY

Ulian-Benitez

Bishop

Földi

et al. 2017

Preprint

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Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signalling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). Starting with an unbiased approach, we tested the evelen LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 was expressed in the CNS, could interact genetically with DNTs and could bind DNT2 both in signaling essays and in co-immunoprecipitations. There is promiscuity in ligand binding, as Kek-6 could also bind DNT1, and Kek-5 could also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and binds DNT2 produced by the muscle, which functions as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth, bouton formation and active zone homeostasis. Kek-6 does not antagonise the alternative DNT2 receptor Toll-6, but rather the two receptors contribute in distinct manners to NMJ structural plasticity. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that together they regulate NMJ growth and active zone formation. These functions of Kek-6 could be evolutionarily conserved, raising the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain.AUTHOR SUMMARYA long-standing paradox had been to explain how brain structural plasticity, learning and long-term memory might occur in Drosophila in the absence of canonical Trk receptors for neurotrophin (NT) ligands. NTs link structure and function in the brain enabling adjustments in cell number, dendritic, axonal and synaptic patterns, in response to neuronal activity. These events are essential for brain development, learning and long-term memory, and are thought to depend on the tyrosine-kinase function of the NT Trk receptors. However, paradoxically, the most abundant Trk isoforms in the adult human brain lack the tyrosine kinase, and their neuronal function is unknown. Remarkably, Drosophila has kinase-less receptors of the Trk family encoded by the kekkon (kek) genes, suggesting that deep evolutionary functional conservation for this receptor class could be unveiled. Here, we show that Kek-6 is a receptor for Drosophila neurotrophin 2 (DNT2) that regulates structural synaptic plasticity via CaMKII and VAP33A, well-known factors regulating synaptic structure and plasticity, and vesicle release. Our findings suggest that in mammals truncated Trk-family receptors could also have synaptic functions in neurons independently of Tyrosine kinase signalling. This might reveal a novel mechanism of brain plasticity, with important implications for understanding also the human brain, in health and disease.

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SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity

Chen,

Lu,

Chen

et al. 2024

The Journal of Gene Medicine

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BackgroundEsophageal squamous cell carcinoma (ESCC) is a predominant subtype of esophageal cancer with relatively high mortality worldwide. Serine peptidase inhibitor Kazal‐type 5 (SPINK5) is reported to be downregulated in ESCC. However, its explicit role in ESCC remains further investigation.MethodsThe tumor tissues and adjacent non‐cancerous tissues were obtained from 196 patients with ESCC for the determination of SPINK5 mRNA levels. Additionally, the relationship between SPINK5 mRNA levels and clinicopathological features of ESCC patients was explored. The effects of SPINK5 on the invasion and migration of ESCC cells were assessed using Transwell assays. Furthermore, SPINK5 mRNA and LEKTI protein were measured in ESCC cell lines after treatment with poly (I:C), lipopolysaccharide (LPS) or unmethylated CpG DNA. Moreover, the correlation between expression of SPINK5 and nuclear factor‐kappa B (NF‐κB) signaling pathway‐related genes was analyzed in the TCGA‐ESCC cohort, and the effects of SPINK5 on NF‐κB transcription was analyzed using a luciferase reporter gene assay. Finally, the correlations between SPINK5 and infiltration of immune cells, immune scores, stromal scores and ESTIMATE (i.e., Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) scores were explored.ResultsSPINK5 mRNA levels were downregulated in tumor tissues, which was significantly correlated with higher lymph node metastases. Overexpressed SPINK5 inhibited cell invasion and migration in ESCC cell lines. Mechanistically, LPS‐induced activation of Toll‐like receptor 4 (TLR4) decreased SPINK5 mRNA and LEKTI in KYSE150 and KYSE70 cells. Spearman correlation analysis revealed that SPINK5 mRNA was significantly negatively correlated with a total of seven NF‐κB signaling pathway‐related genes in TCGA‐ESCC patients. Moreover, downregulation of SPINK5 increased and upregulation of SPINK5 decreased the activity of the NF‐κB promoter in HEK293T cells. Finally, immune cells infiltration analysis revealed that SPINK5 was significantly correlated with the infiltration of various immune cells, stromal scores, immune scores and ESTIMATE scores.ConclusionsSPINK5 plays critical roles in the TLR4/NF‐κB pathway and immune cells infiltration, which might contribute to the ESCC metastasis. The findings of the present study may provide a promising biomarker for the diagnosis and treatment of esophageal squamous cell carcinoma.

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Three-tier regulation of cell number plasticity by neurotrophins and Tolls in Drosophila

Cited by 37 publications

References 76 publications

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

Dying Neurons Utilize Innate Immune Signaling to Prime Glia for Phagocytosis during Development

KEK-6: A TRUNCATED-TRK-LIKE RECEPTOR FORDROSOPHILANEUROTROPHIN 2 REGULATES STRUCTURAL SYNAPTIC PLASTICITY

SPINK5 inhibits esophageal squamous cell carcinoma metastasis via immune activity

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