Interactions between semaphorins and plexin–neuropilin receptor complexes in the membranes of live cells

Christie, Shaun M.; Hao, Jing; Tracy, Erin; Buck, Matthias; Yu, Jennifer; Smith, Adam W.

doi:10.1016/j.jbc.2021.100965

Cited by 12 publications

(10 citation statements)

References 76 publications

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“…Ucp1 ) is the modulation of their transcriptional levels by thermogenic cues in response to sympathetic outflow and consequent β-adrenoceptor activation [95]. Intriguingly, we found that the mRNA levels of Sema4b and its known receptors (Plexins) and co-receptors (Neuropilins [96]) were significantly downregulated in response to NE stimulation of primary inguinal and brown mouse adipocytes ( Fig. 5D ).…”

Section: Resultsmentioning

confidence: 82%

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Amin

Badenes

Tueshaus

et al. 2022

Preprint

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Objective: The metalloprotease ADAM17 (also called TACE) plays fundamental roles in homeostasis by shedding key signaling molecules from the cell surface. Although its importance for the immune system and epithelial tissues is well-documented, little is known about the role of ADAM17 in metabolic homeostasis. The purpose of this study was to determine the impact of ADAM17 expression, specifically in adipose tissues, on metabolic homeostasis. Methods: We used histopathology, molecular, proteomic, transcriptomic, in vivo integrative physiological and ex vivo biochemical approaches to determine the impact of adipose tissue-specific deletion of ADAM17 upon adipocyte and whole organism metabolic physiology. Results: ADAM17adipoq-creΔ/Δ mice exhibited a hypermetabolic phenotype characterized by elevated energy consumption and increased levels of adipocyte thermogenic gene expression. On a high fat diet, these mice were more thermogenic, while exhibiting elevated expression levels of genes associated with lipid oxidation and lipolysis. This hypermetabolic phenotype protected mutant mice from obesogenic challenge, limiting weight gain, hepatosteatosis and insulin resistance. Activation of beta-adrenoceptors by the neurotransmitter norepinephrine, a key regulator of adipocyte physiology, triggered the shedding of ADAM17 substrates, and regulated ADAM17 expression at the mRNA and protein levels, hence identifying a functional connection between thermogenic licensing and the regulation of ADAM17. Proteomic studies identified Semaphorin 4B (SEMA4B), as a novel ADAM17-shed adipokine, whose expression is regulated by physiological thermogenic cues that acts to dampen thermogenic responses in adipocytes. Transcriptomic data showed that cleaved SEMA4B acts in an autocrine manner in brown adipocytes to dampen the expression of genes involved in thermogenesis, adipogenesis, lipid uptake, storage and catabolism. Conclusion: Our findings identify a novel ADAM17-dependent axis, regulated by beta-adrenoceptors and mediated by the ADAM17-cleaved form of SEMA4B, that may act to limit uncontrolled energy depletion during thermogenesis.

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Section: Resultsmentioning

confidence: 82%

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Amin

Badenes

Tueshaus

et al. 2022

Preprint

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“…Sema3A is an alternative ligand for NRP1. Several studies have indicated that Sema3A can bind to NRP1 and activate signal transduction mediated by NRP1-plexin interplay [ 33 ]. However, the interactions between NRP1 and its ligands and plexins in the process of wound healing are not fully understood.…”

Section: Resultsmentioning

confidence: 99%

Regulation of Semaphorin3A in the process of cutaneous wound healing

et al. 2022

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Semaphorin 3A (Sema3A) has been recognized as a crucial regulator of morphogenesis and homeostasis over a wide range of organ systems. However, its function in cutaneous wound healing is poorly understood. In our study, we demonstrated that Sema3A adenovirus plasmids transfection limited keratinocyte proliferation and decreased migrative capacity as assessed by in vitro wound healing assay. Sema3A transduction inhibited TGF-β1-mediated keratinocyte migration and EMT process. Besides, we applied mice with K14-Cre-mediated deletion of Sema3A and found that Sema3A depletion postponed wound closure with decreased re-epithelialization and matrix growth. Contrary to the results obtained with full-length Sema3A plasmids transfection, increased keratinocyte migration with recombinant Sema3A proteins resulted in quicker closure of the wounding area after a scratch. Further, exogenously applied recombinant Sema3A worked with EGF to maintain the activation of EGFR by interacting with NRP1 and thereby regulated the internalization of the EGFR-NRP1 complex. Taken together, these results indicated a paradoxical role of autonomous and non-autonomous Sema3A expression during wound healing. Combined administration of recombinant EGF and Sema3A proteins could accelerate the process of wound repair, thus providing promising treatment prospects in the future.

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“…4c, 5c). Sema3c encodes the Sema3c secreted ligand, which interacts with receptors PlexinD1 and Nrp1 38,43 . Recombinant Sema3c can stimulate branching morphogenesis of mouse metanephros in ex-vivo organ culture, and conversely, Sema3a/Sema3c double null metanephros show decreased branching morphogenesis compared to wild-type 44 .…”

Section: Discussionmentioning

confidence: 99%

Multiomics analysis reveals that hepatocyte nuclear factor 1β regulates axon guidance genes in the developing mouse kidney

Shao

Gearhart²,

Chan³

et al. 2022

Sci Rep

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The transcription factor hepatocyte nuclear factor 1β (HNF-1β) is essential for normal development of the kidney and other epithelial organs. In the developing mouse kidney, HNF-1β is required for the differentiation and patterning of immature nephrons and branching morphogenesis of the ureteric bud (UB). Here, we used ChIP-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to identify genes that are regulated by HNF-1β in embryonic mouse kidneys. ChIP-seq revealed that HNF-1β binds to 8284 sites in chromatin from E14.5 mouse kidneys. Comparison with previous ATAC-seq and histone modification studies showed that HNF-1β binding peaks colocalized with open chromatin and epigenetic marks of transcriptional activation (H3K27 acetylation, H3K4 trimethylation, H3K4 monomethylation), indicating that the binding sites were functional. To investigate the relationship between HNF-1β binding and HNF-1β-dependent gene regulation, RNA-seq was performed on UB cells purified from wild-type and HNF-1β mutant embryonic kidneys. A total of 1632 genes showed reduced expression in HNF-1β-deficient UB cells, and 485 genes contained nearby HNF-1β binding sites indicating that they were directly activated by HNF-1β. Conversely, HNF-1β directly repressed the expression of 526 genes in the UB. Comparison with snATAC-seq analysis of UB-derived cells showed that both HNF-1β-dependent activation and repression correlated with chromatin accessibility. Pathway analysis revealed that HNF-1β binds near 68 axon guidance genes in the developing kidney. RNA-seq analysis showed that Nrp1, Sema3c, Sema3d, Sema6a, and Slit2 were activated by HNF-1β, whereas Efna1, Epha3, Epha4, Epha7, Ntn4, Plxna2, Sema3a, Sema4b, Slit3, Srgap1, Unc5c and Unc5d were repressed by HNF-1β. RNAscope in situ hybridization showed that Nrp1, Sema3c, Sema3d, Sema6a, and Slit2 were expressed in wild-type UB and were dysregulated in HNF-1β mutant UB. These studies show that HNF-1β directly regulates the expression of multiple axon guidance genes in the developing mouse kidney. Dysregulation of axon guidance genes may underlie kidney defects in HNF-1β mutant mice.

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Interactions between semaphorins and plexin–neuropilin receptor complexes in the membranes of live cells

Cited by 12 publications

References 76 publications

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Semaphorin 4B is an ADAM17-cleaved inhibitor of adipocyte thermogenesis

Regulation of Semaphorin3A in the process of cutaneous wound healing

Multiomics analysis reveals that hepatocyte nuclear factor 1β regulates axon guidance genes in the developing mouse kidney

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