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1.
Cell Rep ; 42(9): 113137, 2023 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-37708022

RESUMEN

As cerebellar granule cells (GCs) coordinate the formation of regular cerebellar networks during postnatal development, molecules in GCs are expected to be involved. Here, we test the effects of the knockdown (KD) of multiple epidermal growth factor-like domains protein 11 (MEGF11), which is a homolog of proteins mediating astrocytic phagocytosis but is substantially increased at the later developmental stages of GCs on cerebellar development. MEGF11-KD in GCs of developing mice results in abnormal cerebellar structures, including extensively ectopic Purkinje cell (PC) somas, and in impaired motor functions. MEGF11-KD also causes abnormally asynchronous synaptic release from GC axons, parallel fibers, before the appearance of abnormal cerebellar structures. Interestingly, blockade of this abnormal synaptic release restores most of the cerebellar structures. Thus, apart from phagocytic functions of its related homologs in astrocytes, MEGF11 in GCs promotes proper PC development and cerebellar network formation by regulating immature synaptic transmission.

2.
Front Mol Neurosci ; 16: 1236015, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37520428

RESUMEN

The well-organized cerebellar structures and neuronal networks are likely crucial for their functions in motor coordination, motor learning, cognition, and emotion. Such cerebellar structures and neuronal networks are formed during developmental periods through orchestrated mechanisms, which include not only cell-autonomous programs but also interactions between the same or different types of neurons. Cerebellar granule cells (GCs) are the most numerous neurons in the brain and are generated through intensive cell division of GC precursors (GCPs) during postnatal developmental periods. While GCs go through their own developmental processes of proliferation, differentiation, migration, and maturation, they also play a crucial role in cerebellar development. One of the best-characterized contributions is the enlargement and foliation of the cerebellum through massive proliferation of GCPs. In addition to this contribution, studies have shown that immature GCs and GCPs regulate multiple factors in the developing cerebellum, such as the development of other types of cerebellar neurons or the establishment of afferent innervations. These studies have often found impairments of cerebellar development in animals lacking expression of certain molecules in GCs, suggesting that the regulations are mediated by molecules that are secreted from or present in GCs. Given the growing recognition of GCs as regulators of cerebellar development, this review will summarize our current understanding of cerebellar development regulated by GCs and molecules in GCs, based on accumulated studies and recent findings, and will discuss their potential further contributions.

3.
Anat Sci Int ; 95(2): 230-239, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31848974

RESUMEN

Peripheral neurodegenerative processes are essential for regenerating damaged peripheral nerves mechanically or genetically. Abnormal neurodegenerative processes induce peripheral neurodegenerative diseases via irreversible nerve damage. Carvacrol, a major component in Origanum vulgare, possesses various effects on organisms, such as antibiotic, anti-inflammatory and cytoprotective effects; although transient receptor potential (TRP) ankyrin 1 (TRPA1), TRP canonical 1 (TRPC1), TRP melastatin M7 (TRPM7), and TRP vanilloid 3 (TRPV3) are carvacrol-regulated TRPs, however, effect of carvacrol on the peripheral neurodegenerative process, and its underlying mechanism, remain unclear. Here, we investigated the specificity of carvacrol for TRPM7 in Schwann cells and the regulatory effect of carvacrol on TRPM7-dependent neurodegenerative processes. To construct peripheral nerve degeneration model, we used with a sciatic explant culture and sciatic nerve axotomy. Ex vivo, in vivo sciatic nerves were treated with carvacrol following an assessment of demyelination (ovoid fragmentation) and axonal degradation using morphometric indices. In these models, carvacrol effectively suppressed the morphometric indices, such as stripe, ovoid, myelin, and neurofilament indices during peripheral nerve degeneration. We found that carvacrol significantly inhibited upregulation of TRPM7 in Schwann cells. In this study, our results suggest that carvacrol effectively protects against the peripheral neurodegenerative process via TRPM7-dependent regulation in Schwann cells. Thus, pharmacological use of carvacrol could be helpful to protect against neurodegeneration that occurs with aging and peripheral neurodegenerative diseases, prophylactically.


Asunto(s)
Cimenos/farmacología , Cimenos/uso terapéutico , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/prevención & control , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/prevención & control , Fitoterapia , Proteínas Serina-Treonina Quinasas/metabolismo , Células de Schwann/metabolismo , Canales Catiónicos TRPM/metabolismo , Células Cultivadas , Cimenos/aislamiento & purificación , Humanos , Origanum/química , Células de Schwann/patología , Nervio Ciático , Regulación hacia Arriba/efectos de los fármacos
4.
Neurochem Res ; 44(8): 1964-1976, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31218567

RESUMEN

Schwann cells are essential glial cells in the peripheral nervous system (PNS), and dysfunction of Schwann cells can induce various peripheral neurodegenerative diseases. Oxidative stress has been implicated as a causative factor in degenerative nerve diseases; however, there no effective molecules are available to inhibit nerve degeneration in peripheral neurodegenerative diseases. Ethyl pyruvate (EP) is a candidate regulator of oxidative stress, targeting Schwann cells during peripheral nerve degeneration. Here, we investigated the effects of EP on axonal degradation, demyelination, transcriptional regulation, and macrophage recruitment during Wallerian degeneration of the sciatic nerve, ex vivo and in vivo. EP prevented the expression of neuronal nitric oxide synthase (NOS1), but not that of inducible nitric oxide synthase (NOS2), during Wallerian degeneration. These results suggest that effect of EP on Schwann cells may protect against peripheral nerve degeneration through its NOS1-specific regulation.


Asunto(s)
Inhibidores Enzimáticos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Piruvatos/uso terapéutico , Células de Schwann/efectos de los fármacos , Degeneración Walleriana/prevención & control , Animales , Axones/efectos de los fármacos , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/prevención & control , Macrófagos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Vaina de Mielina/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/patología , Degeneración Walleriana/patología
5.
ASN Neuro ; 11: 1759091419838949, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31046408

RESUMEN

During Wallerian degeneration, Schwann cells lose their characteristic of myelinating axons and shift into the state of developmental promyelinating cells. This recharacterized Schwann cell guides newly regrowing axons to their destination and remyelinates reinnervated axons. This Schwann cell dynamics during Wallerian degeneration is associated with oxidative events. Heme oxygenases (HOs) are involved in the oxidative degradation of heme into biliverdin/bilirubin, ferrous iron, and carbon monoxide. Overproduction of ferrous iron by HOs increases reactive oxygen species, which have deleterious effects on living cells. Thus, the key molecule for understanding the exact mechanism of Wallerian degeneration in the peripheral nervous system is likely related to oxidative stress-mediated HOs in Schwann cells. In this study, we demonstrate that demyelinating Schwann cells during Wallerian degeneration highly express HO1, not HO2, and remyelinating Schwann cells during nerve regeneration decrease HO1 activation to levels similar to those in normal myelinating Schwann cells. In addition, HO1 activation during Wallerian degeneration regulates several critical phenotypes of recharacterized repair Schwann cells, such as demyelination, transdedifferentiation, and proliferation. Thus, these results suggest that oxidative stress in Schwann cells after peripheral nerve injury may be regulated by HO1 activation during Wallerian degeneration and oxidative-stress-related HO1 activation in Schwann cells may be helpful to study deeply molecular mechanism of Wallerian degeneration.


Asunto(s)
Hemo Oxigenasa (Desciclizante)/metabolismo , Estrés Oxidativo/fisiología , Células de Schwann/enzimología , Nervio Ciático/enzimología , Degeneración Walleriana/enzimología , Animales , Monóxido de Carbono/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Masculino , Regeneración Nerviosa/fisiología , Ratas Sprague-Dawley , Células de Schwann/patología , Nervio Ciático/lesiones , Nervio Ciático/patología , Técnicas de Cultivo de Tejidos , Degeneración Walleriana/patología
6.
Materials (Basel) ; 12(7)2019 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-30939730

RESUMEN

Aminoacyl-tRNA synthetase-interacting multifunctional proteins (AIMPs) are auxiliary factors involved in protein synthesis related to aminoacyl-tRNA synthetases (ARSs). AIMPs, which are well known as nonenzymatic factors, include AIMP1/p43, AIMP2/p38, and AIMP3/p18. The canonical functions of AIMPs include not only protein synthesis via multisynthetase complexes but also maintenance of the structural stability of these complexes. Several recent studies have demonstrated nontypical (noncanonical) functions of AIMPs, such as roles in apoptosis, inflammatory processes, DNA repair, and so on. However, these noncanonical functions of AIMPs have not been studied in peripheral nerves related to motor and sensory functions. Peripheral nerves include two types of structures: peripheral axons and Schwann cells. The myelin sheath formed by Schwann cells produces saltatory conduction, and these rapid electrical signals control motor and sensory functioning in the service of survival in mammals. Schwann cells play roles not only in myelin sheath formation but also as modulators of nerve degeneration and regeneration. Therefore, it is important to identify the main functions of Schwann cells in peripheral nerves. Here, using immunofluorescence technique, we demonstrated that AIMPs are essential morphological indicators of peripheral nerve degeneration, and their actions are limited to peripheral nerves and not the dorsal root ganglion and the ventral horn of the spinal cord.

7.
Anat Sci Int ; 94(4): 285-294, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30949912

RESUMEN

Oxidative stress contributes to the progression of neurodegenerative diseases of the central and peripheral nervous systems, including Alzheimer's disease, Parkinson's disease, stroke, and diabetic neuropathy. Despite the greater capability of peripheral nerves to regenerate compared with those in the brain or spinal cord, chronic oxidative stress leads to irreversible neurodegeneration in peripheral nerves. Thus, many efforts have been made to defend against irreversible peripheral nerve degeneration and oxidative stress. Numerous phytochemicals have been revealed as antioxidants which neutralize free radicals and reduce peripheral neurocellular damage. Among them, polyphenols alleviate neurodegeneration by interacting with reactive oxygen species. Apigenin is a polyphenol found in plant-derived foods, including parsley, thyme, celery, and chamomile tea. Apigenin has been reported to exert antioxidative effects by scavenging free radicals. In particular, apigenin has a neuroprotective effect against oxidative stress in neurological disorders, such as cerebral ischemia. However, to date, no studies have shown an association of the inhibitory effect of apigenin with peripheral nerve degeneration. In this work, we showed that apigenin has a neuroprotective effect against peripheral nerve degeneration according to four key phenotypes: axonal degradation, myelin fragmentation, trans-dedifferentiation, and proliferation of Schwann cells via Krox20- and extracellular signal-regulated kinase-independent processes. Thus, apigenin could be a good candidate to treat peripheral neurodegenerative diseases.


Asunto(s)
Apigenina/farmacología , Depuradores de Radicales Libres/farmacología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Animales , Apigenina/uso terapéutico , Axones/efectos de los fármacos , Axones/patología , Desdiferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Depuradores de Radicales Libres/uso terapéutico , Humanos , Masculino , Ratones , Enfermedades Neurodegenerativas/patología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/patología , Especies Reactivas de Oxígeno/metabolismo , Células de Schwann/efectos de los fármacos , Células de Schwann/patología , Nervio Ciático/patología
8.
J Mol Histol ; 50(2): 167-178, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30671879

RESUMEN

Peripheral nerves, which consist of an axon and a unique glial cell called a Schwann cell, transduce signals from the brain and spinal cord to target organs. Peripheral nerve degeneration leads to distal motor or sensory disorders such as diabetic neuropathy, Charcot-Marie-Tooth disease, and Gullain-Barré syndrome, with symptoms such as dysesthesia, speech impairment, vision change, erectile dysfunction, and urinary incontinence. Schwann cells play an important role in peripheral nerve degeneration. Therefore, revealing the characteristics of Schwann cells will be essential in understanding peripheral neurodegeneration-related diseases for which there is currently no effective treatment. Trichostatin A (TSA) is a noncompetitive, reversible inhibitor of class I and II histone deacetylases (HDACs). HDACs have been shown not only to deacetylate histones but also to target non-histone proteins involved in diverse signaling pathways. Recent studies have revealed that diverse HDAC subtypes regulate peripheral neurodegeneration. Thus, regulating HDAC levels could be an effective strategy for the development of drugs targeting peripheral nerve-related diseases. In fact, the use of TSA has been investigated for the treatment of many diseases, including degenerative diseases of the central nervous system; however, the effects of TSA on peripheral neurodegeneration have not yet been well established. In this study, we revealed the effect of TSA on the process of peripheral neurodegeneration. TSA successfully inhibited myelin fragmentation, axonal degradation, and trans-dedifferentiation and proliferation of Schwann cells, which are essential phenotypes in peripheral neurodegeneration. Therefore, TSA could be a potential drug for patients suffering from peripheral neurodegeneration-related diseases.


Asunto(s)
Inhibidores de Histona Desacetilasas/farmacología , Ácidos Hidroxámicos/farmacología , Degeneración Nerviosa/prevención & control , Enfermedades del Sistema Nervioso Periférico/prevención & control , Axones/efectos de los fármacos , Axones/metabolismo , Desdiferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Humanos , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/metabolismo , Células de Schwann/patología
9.
Adv Mater ; 29(39)2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28833739

RESUMEN

A major obstacle in luminescence imaging is the limited penetration of visible light into tissues and interference associated with light scattering and autofluorescence. Near-infrared (NIR) emitters that can also be excited with NIR radiation via two-photon processes can mitigate these factors somewhat because they operate at wavelengths of 650-1000 nm where tissues are more transparent, light scattering is less efficient, and endogenous fluorophores are less likely to absorb. This study presents photolytically stable, NIR photoluminescent, porous silicon nanoparticles with a relatively high two-photon-absorption cross-section and a large emission quantum yield. Their ability to be targeted to tumor tissues in vivo using the iRGD targeting peptide is demonstrated, and the distribution of the nanoparticles with high spatial resolution is visualized.

10.
J Fluoresc ; 27(6): 2231-2238, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28823107

RESUMEN

8-Amino-BODIPY (boron-dipyrromethane) dyes show bright blue fluorescence. Disclosed here are synthesis and characterization of the photophysical properties of a series of functionalized 8-Amino-BODIPY (BP1-4) for protein labeling. The compact structure and solvent-insensitive absorption property of the dye are desirable features for protein labeling. For the model protein, bovine serum albumin (BSA), the labeling proceeds under mild condition via amide bond formation or thiol-ene conjugation with maintaining the bright blue fluorescence. The chromatography and mass spectroscopy analysis clearly support the labeling of the BODIPY dye on the BSA. The protein labeling with blue-emitting BODIPY would be applicable for studying protein dynamics and fluorescence resonance energy transfer (FRET) with intrinsic biomolecules.


Asunto(s)
Compuestos de Boro/química , Fluorescencia , Colorantes Fluorescentes/química , Albúmina Sérica Bovina/química , Animales , Bovinos , Transferencia Resonante de Energía de Fluorescencia , Modelos Moleculares
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