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Nature Communications Jun 2023Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived...
Brown adipose tissue (BAT)-mediated thermogenesis declines with age. However, the underlying mechanism remains unclear. Here we reveal that bone marrow-derived pro-inflammatory and senescent S100A8 immune cells, mainly T cells and neutrophils, invade the BAT of male rats and mice during aging. These S100A8 immune cells, coupled with adipocytes and sympathetic nerves, compromise axonal networks. Mechanistically, these senescent immune cells secrete abundant S100A8 to inhibit adipose RNA-binding motif protein 3 expression. This downregulation results in the dysregulation of axon guidance-related genes, leading to impaired sympathetic innervation and thermogenic function. Xenotransplantation experiments show that human S100A8 immune cells infiltrate mice BAT and are sufficient to induce aging-like BAT dysfunction. Notably, treatment with S100A8 inhibitor paquinimod rejuvenates BAT axon networks and thermogenic function in aged male mice. Our study suggests that targeting the bone marrow-derived senescent immune cells presents an avenue to improve BAT aging and related metabolic disorders.
Topics: Male; Mice; Humans; Rats; Animals; Aged; Adipose Tissue, Brown; Thermogenesis; Adiposity; Obesity; Aging; Adipocytes, Brown
PubMed: 37268694
DOI: 10.1038/s41467-023-38842-6 -
Nature Jul 2023The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes...
The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.
Topics: Humans; Brain; Brain Neoplasms; Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic; Glioblastoma; Glioma; Neurons; Tumor Microenvironment; Cell Proliferation; Synapses; Disease Progression; Animals; Mice; Axons; Corpus Callosum; Neural Pathways
PubMed: 37380778
DOI: 10.1038/s41586-023-06267-2 -
Frontiers in Neuroscience 2023Neuronal migration and axon growth and guidance require precise control of microtubule dynamics and microtubule-based cargo transport. encodes the neuronal-specific... (Review)
Review
Neuronal migration and axon growth and guidance require precise control of microtubule dynamics and microtubule-based cargo transport. encodes the neuronal-specific β-tubulin isotype III, TUBB3, a component of neuronal microtubules expressed throughout the life of central and peripheral neurons. Human pathogenic missense variants result in altered TUBB3 function and cause errors either in the growth and guidance of cranial and, to a lesser extent, central axons, or in cortical neuronal migration and organization, and rarely in both. Moreover, human pathogenic missense variants in , which encodes an anterograde kinesin motor protein that interacts directly with microtubules, alter KIF21A function and cause errors in cranial axon growth and guidance that can phenocopy variants. Here, we review reported and variants, resulting phenotypes, and corresponding functional studies of both wildtype and mutant proteins. We summarize the evidence that, and in mouse models, loss-of-function and missense variants can alter microtubule dynamics and microtubule-kinesin interactions. Lastly, we highlight additional studies that might contribute to our understanding of the relationship between specific tubulin isotypes and specific kinesin motor proteins in health and disease.
PubMed: 37600020
DOI: 10.3389/fnins.2023.1226181 -
Journal of Molecular Biology Feb 2024UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the... (Review)
Review
UNC-51-like kinases 1 and 2 (ULK1/2) are serine/threonine kinases that are best known for their evolutionarily conserved role in the autophagy pathway. Upon sensing the nutrient status of a cell, ULK1/2 integrate signals from upstream cellular energy sensors such as mTOR and AMPK and relay them to the downstream components of the autophagy machinery. ULK1/2 also play indispensable roles in the selective autophagy pathway, removing damaged mitochondria, invading pathogens, and toxic protein aggregates. Additional functions of ULK1/2 have emerged beyond autophagy, including roles in protein trafficking, RNP granule dynamics, and signaling events impacting innate immunity, axon guidance, cellular homeostasis, and cell fate. Therefore, it is no surprise that alterations in ULK1/2 expression and activity have been linked with pathophysiological processes, including cancer, neurological disorders, and cardiovascular diseases. Growing evidence suggests that ULK1/2 function as biological rheostats, tuning cellular functions to intra and extra-cellular cues. Given their broad physiological relevance, ULK1/2 are candidate targets for small molecule activators or inhibitors that may pave the way for the development of therapeutics for the treatment of diseases in humans.
PubMed: 38311233
DOI: 10.1016/j.jmb.2024.168472 -
BioRxiv : the Preprint Server For... Oct 2023Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes....
UNLABELLED
Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the gene from the and mutation knock-in, (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher expression with an increase in and expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is "hijacked" by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation.
ONE SENTENCE SUMMARY
Tumor- and nerve-derived SEMA3D promotes tumor progression and metastasis through macrophage reprogramming in the tumor microenvironment.
STATEMENT OF SIGNIFICANCE
This study established the dual role of axon guidance molecule, SEMA3D, in the malignant transformation of pancreatic epithelial cells and of nerve-derived SEMA3D in PDA progression and metastasis. It revealed macrophage reprogramming as the mechanism underlying bothroles. Together, this research elucidated how inflammatory responses promote invasive PDA progression and metastasis through an oncogenic process.
PubMed: 37961340
DOI: 10.1101/2023.10.24.563862 -
International Journal of Molecular... Jun 2023Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival,... (Review)
Review
Fibroblast growth factors (FGFs) have been widely studied by virtue of their ability to regulate many essential cellular activities, including proliferation, survival, migration, differentiation and metabolism. Recently, these molecules have emerged as the key components in forming the intricate connections within the nervous system. FGF and FGF receptor (FGFR) signaling pathways play important roles in axon guidance as axons navigate toward their synaptic targets. This review offers a current account of axonal navigation functions performed by FGFs, which operate as chemoattractants and/or chemorepellents in different circumstances. Meanwhile, detailed mechanisms behind the axon guidance process are elaborated, which are related to intracellular signaling integration and cytoskeleton dynamics.
Topics: Fibroblast Growth Factors; Receptors, Fibroblast Growth Factor; Axon Guidance; Signal Transduction; Axons
PubMed: 37373438
DOI: 10.3390/ijms241210292 -
Biology Jul 2023Integrin receptors are essential contributors to neurite outgrowth and axon elongation. Activated integrins engage components of the extracellular matrix, enabling the... (Review)
Review
Integrin receptors are essential contributors to neurite outgrowth and axon elongation. Activated integrins engage components of the extracellular matrix, enabling the growth cone to form point contacts, which connect the extracellular substrate to dynamic intracellular protein complexes. These adhesion complexes facilitate efficient growth cone migration and neurite extension. Major signalling pathways mediated by the adhesion complex are instigated by focal adhesion kinase (FAK), whilst axonal guidance molecules present in vivo promote growth cone turning or retraction by local modulation of FAK activity. Activation of FAK is marked by phosphorylation following integrin engagement, and this activity is tightly regulated during neurite outgrowth. FAK inhibition slows neurite outgrowth by reducing point contact turnover; however, mutant FAK constructs with enhanced activity stimulate aberrant outgrowth. Importantly, FAK is a major structural component of maturing adhesion sites, which provide the platform for actin polymerisation to drive leading edge advance. In this review, we discuss the coordinated signalling of integrin receptors and FAK, as well as their role in regulating neurite outgrowth and axon elongation. We also discuss the importance of the integrin-FAK axis in vivo, as integrin expression and activation are key determinants of successful axon regeneration following injury.
PubMed: 37508384
DOI: 10.3390/biology12070954 -
Brain and Behavior Sep 2023The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo... (Review)
Review
BACKGROUND
The brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo type mechanosensitive ion channel component 1 (Piezo1), a protein found in metazoans, is highly expressed in the brain and involved in sensing changes of the mechanical microenvironment. Numerous studies have shown that Piezo1-mediated mechanotransduction is closely related to glial cell activation and neuronal function. However, the precise role of Piezo1 in the brain requires further elucidation.
OBJECTIVE
This review first discusses the roles of Piezo1-mediated mechanotransduction in regulating the functions of a variety of brain cells, and then briefly assesses the impact of Piezo1-mediated mechanotransduction on the progression of brain dysfunctional disorders.
CONCLUSIONS
Mechanical signaling contributes significantly to brain function. Piezo1-mediated mechanotransduction regulates processes such as neuronal differentiation, cell migration, axon guidance, neural regeneration, and oligodendrocyte axon myelination. Additionally, Piezo1-mediated mechanotransduction plays significant roles in normal aging and brain injury, as well as the development of various brain diseases, including demyelinating diseases, Alzheimer's disease, and brain tumors. Investigating the pathophysiological mechanisms through which Piezo1-mediated mechanotransduction affects brain function will give us a novel entry point for the diagnosis and treatment of numerous brain diseases.
Topics: Humans; Axons; Brain; Brain Neoplasms; Mechanotransduction, Cellular; Neurons; Tumor Microenvironment
PubMed: 37366640
DOI: 10.1002/brb3.3136 -
Frontiers in Immunology 2023Platelets are anucleate blood cells derived from megakaryocytes. They link the fundamental functions of hemostasis, inflammation and host defense. They undergo... (Review)
Review
Platelets are anucleate blood cells derived from megakaryocytes. They link the fundamental functions of hemostasis, inflammation and host defense. They undergo intracellular calcium flux, negatively charged phospholipid translocation, granule release and shape change to adhere to collagen, fibrin and each other, forming aggregates, which are key to several of their functions. In all these dynamic processes, the cytoskeleton plays a crucial role. Neuronal guidance proteins (NGPs) form attractive and repulsive signals to drive neuronal axon navigation and thus refine neuronal circuits. By binding to their target receptors, NGPs rearrange the cytoskeleton to mediate neuron motility. In recent decades, evidence has indicated that NGPs perform important immunomodulatory functions and influence platelet function. In this review, we highlight the roles of NGPs in platelet formation and activation.
Topics: Humans; Axon Guidance; Blood Platelets; Hemostasis; Megakaryocytes; Inflammation
PubMed: 37398659
DOI: 10.3389/fimmu.2023.1206906 -
Frontiers in Cellular Neuroscience 2023Glia and neurons are intimately associated throughout bilaterian nervous systems, and were early proposed to interact for patterning circuit assembly. The investigations... (Review)
Review
Glia and neurons are intimately associated throughout bilaterian nervous systems, and were early proposed to interact for patterning circuit assembly. The investigations of circuit formation progressed from early hypotheses of intermediate guideposts and a "glia blueprint", to recent genetic and cell manipulations, and visualizations . An array of molecular factors are implicated in axon pathfinding but their number appears small relatively to circuit complexity. Comprehending this circuit complexity requires to identify unknown factors and dissect molecular topographies. Glia contribute to both aspects and certain studies provide molecular and functional insights into these contributions. Here, I survey glial roles in guiding axon navigation , emphasizing analogies, differences and open questions across major genetic models. I highlight studies pioneering the topic, and dissect recent findings that further advance our current molecular understanding. Circuits of the vertebrate forebrain, visual system and neural tube in zebrafish, mouse and chick, the ventral cord and the brain-like neuropil emerge as major contexts to study glial cell functions in axon navigation. I present astroglial cell types in these models, and their molecular and cellular interactions that drive axon guidance. I underline shared principles across models, conceptual or technical complications, and open questions that await investigation. Glia of the radial-astrocyte lineage, emerge as regulators of axon pathfinding, often employing common molecular factors across models. Yet this survey also highlights different involvements of glia in embryonic navigation or pioneer axon pathfinding, and unknowns in the molecular underpinnings of glial cell functions. Future cellular and molecular investigations should complete the comprehensive view of glial roles in circuit assembly.
PubMed: 37941606
DOI: 10.3389/fncel.2023.1241957