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1.
Cell ; 168(1-2): 252-263.e14, 2017 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-28017328

RESUMEN

Signaling receptors dynamically exit cilia upon activation of signaling pathways such as Hedgehog. Here, we find that when activated G protein-coupled receptors (GPCRs) fail to undergo BBSome-mediated retrieval from cilia back into the cell, these GPCRs concentrate into membranous buds at the tips of cilia before release into extracellular vesicles named ectosomes. Unexpectedly, actin and the actin regulators drebrin and myosin 6 mediate ectosome release from the tip of cilia. Mirroring signal-dependent retrieval, signal-dependent ectocytosis is a selective and effective process that removes activated signaling molecules from cilia. Congruently, ectocytosis compensates for BBSome defects as ectocytic removal of GPR161, a negative regulator of Hedgehog signaling, permits the appropriate transduction of Hedgehog signals in Bbs mutants. Finally, ciliary receptors that lack retrieval determinants such as the anorexigenic GPCR NPY2R undergo signal-dependent ectocytosis in wild-type cells. Our data show that signal-dependent ectocytosis regulates ciliary signaling in physiological and pathological contexts.


Asunto(s)
Cilios/metabolismo , Vesículas Extracelulares/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Actinas/metabolismo , Animales , Línea Celular , Humanos , Riñón/citología , Riñón/metabolismo , Ratones , Microscopía Electrónica de Rastreo , Receptores de Somatostatina/metabolismo , Transducción de Señal
2.
Nature ; 626(8001): 1056-1065, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38122823

RESUMEN

The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimer's disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.


Asunto(s)
Movimiento Celular , Neuronas , Lóbulo Temporal , Animales , Preescolar , Humanos , Lactante , Corteza Entorrinal/citología , Corteza Entorrinal/fisiología , Eminencia Ganglionar/citología , Interneuronas/citología , Interneuronas/fisiología , Macaca mulatta , Neuronas/citología , Neuronas/fisiología , Análisis de Expresión Génica de una Sola Célula , Lóbulo Temporal/citología , Lóbulo Temporal/crecimiento & desarrollo
3.
Acta Neuropathol ; 148(1): 43, 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39283487

RESUMEN

Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.


Asunto(s)
Esclerosis Amiotrófica Lateral , Proteína Forkhead Box O1 , Músculo Esquelético , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Humanos , Animales , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Masculino , Proteína FUS de Unión a ARN/genética , Proteína FUS de Unión a ARN/metabolismo , Femenino , Drosophila , Desarrollo de Músculos/fisiología , Persona de Mediana Edad , Anciano , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Mioblastos/metabolismo
4.
Cereb Cortex ; 33(21): 10931-10948, 2023 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-37724425

RESUMEN

Adult neurogenesis persists in mammals in the neurogenic zones, where newborn neurons are incorporated into preexisting circuits to preserve and improve learning and memory tasks. Relevant structural elements of the neurogenic niches include the family of cell adhesion molecules (CAMs), which participate in signal transduction and regulate the survival, division, and differentiation of radial glial progenitors (RGPs). Here we analyzed the functions of neural cell adhesion molecule 2 (NCAM2) in the regulation of RGPs in adult neurogenesis and during corticogenesis. We characterized the presence of NCAM2 across the main cell types of the neurogenic process in the dentate gyrus, revealing different levels of NCAM2 amid the progression of RGPs and the formation of neurons. We showed that Ncam2 overexpression in adult mice arrested progenitors in an RGP-like state, affecting the normal course of young-adult neurogenesis. Furthermore, changes in Ncam2 levels during corticogenesis led to transient migratory deficits but did not affect the survival and proliferation of RGPs, suggesting a differential role of NCAM2 in adult and embryonic stages. Our data reinforce the relevance of CAMs in the neurogenic process by revealing a significant role of Ncam2 levels in the regulation of RGPs during young-adult neurogenesis in the hippocampus.


Asunto(s)
Neurogénesis , Neuronas , Ratones , Animales , Neuronas/fisiología , Neurogénesis/fisiología , Diferenciación Celular/fisiología , Moléculas de Adhesión de Célula Nerviosa/metabolismo , Hipocampo/metabolismo , Mamíferos/metabolismo
5.
Mol Psychiatry ; 26(9): 4616-4632, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-32612250

RESUMEN

In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.


Asunto(s)
Neurogénesis , Núcleo Accumbens , Animales , Ventrículos Laterales , Ratones , Neuronas , Bulbo Olfatorio , Dolor
6.
Cereb Cortex ; 30(7): 4092-4109, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32108222

RESUMEN

Even after birth, neuronal production continues in the ventricular-subventricular zone (V-SVZ) and hippocampus in many mammals. The immature new neurons ("neuroblasts") migrate and then mature at their final destination. In humans, neuroblast production and migration toward the neocortex and the olfactory bulb (OB) occur actively only for a few months after birth and then sharply decline with age. However, the precise spatiotemporal profiles and fates of postnatally born neurons remain unclear due to methodological limitations. We previously found that common marmosets, small nonhuman primates, share many features of V-SVZ organization with humans. Here, using marmosets injected with thymidine analogue(s) during various postnatal periods, we demonstrated spatiotemporal changes in neurogenesis during development. V-SVZ progenitor proliferation and neuroblast migration toward the OB and neocortex sharply decreased by 4 months, most strikingly in a V-SVZ subregion from which neuroblasts migrated toward the neocortex. Postnatally born neurons matured within a few months in the OB and hippocampus but remained immature until 6 months in the neocortex. While neurogenic activity was sustained for a month after birth, the distribution and/or differentiation diversity was more restricted in 1-month-born cells than in the neonatal-born population. These findings shed light on distinctive features of postnatal neurogenesis in primates.


Asunto(s)
Proliferación Celular , Hipocampo/crecimiento & desarrollo , Ventrículos Laterales/crecimiento & desarrollo , Neocórtex/crecimiento & desarrollo , Células-Madre Neurales/citología , Neurogénesis , Bulbo Olfatorio/crecimiento & desarrollo , Animales , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Callithrix , Movimiento Celular , Ventrículos Cerebrales/citología , Ventrículos Cerebrales/crecimiento & desarrollo , Hipocampo/citología , Ventrículos Laterales/citología , Neocórtex/citología , Bulbo Olfatorio/citología , Análisis Espacio-Temporal
7.
J Neurosci ; 39(50): 9967-9988, 2019 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-31685650

RESUMEN

New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in migrating neuroblasts in the postnatal RMS and OB. The primary cilium was observed in migrating neuroblasts in the postnatal RMS and OB in male and female mice and zebrafish, and a male rhesus monkey. Inhibition of intraflagellar transport molecules in migrating neuroblasts impaired their ciliogenesis and rostral migration toward the OB. Serial section transmission electron microscopy revealed that each migrating neuroblast possesses either a pair of centrioles or a basal body with an immature or mature primary cilium. Using immunohistochemistry, live imaging, and serial block-face scanning electron microscopy, we demonstrate that the localization and orientation of the primary cilium are altered depending on the mitotic state, saltatory migration, and deceleration of neuroblasts. Together, our results highlight a close mutual relationship between spatiotemporal regulation of the primary cilium and efficient chain migration of neuroblasts in the postnatal brain.SIGNIFICANCE STATEMENT Immature neurons (neuroblasts) generated in the postnatal brain have a mitotic potential and migrate in chain-like cell aggregates toward the olfactory bulb. Here we report that migrating neuroblasts possess a tiny cellular protrusion called a primary cilium. Immunohistochemical studies with zebrafish, mouse, and monkey brains suggest that the presence of the primary cilium in migrating neuroblasts is evolutionarily conserved. Ciliogenesis in migrating neuroblasts in the rostral migratory stream is suppressed during mitosis and promoted after cell cycle exit. Moreover, live imaging and 3D electron microscopy revealed that ciliary localization and orientation change during saltatory movement of neuroblasts. Our results reveal highly organized dynamics in maturation and positioning of the primary cilium during neuroblast migration that underlie saltatory movement of postnatal-born neuroblasts.


Asunto(s)
Movimiento Celular/fisiología , Cilios/ultraestructura , Ventrículos Laterales/ultraestructura , Células-Madre Neurales/ultraestructura , Neuronas/ultraestructura , Bulbo Olfatorio/ultraestructura , Animales , Femenino , Macaca mulatta , Masculino , Ratones , Pez Cebra
8.
J Neurosci ; 38(19): 4598-4609, 2018 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-29661967

RESUMEN

In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and in vivo loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustained at the contact sites between neuroblasts. Moreover, a Fyn and N-cadherin double-knockdown experiment indicated that Fyn regulates the N-cadherin-mediated cell adhesion between neuroblasts. These results suggest that the Fyn-mediated control of cell-cell adhesion is critical for the detachment of chain-forming neuroblasts in the postnatal OB.SIGNIFICANCE STATEMENT In the postnatal brain, newly born neurons (neuroblasts) migrate in chain-like cell aggregates toward their destination, where they are dissociated into individual cells and mature. The cellular and molecular mechanisms controlling the detachment of neuroblasts from chains are not understood. Here we show that Fyn, a nonreceptor tyrosine kinase, promotes the somal detachment of neuroblasts from chains, and that this regulation is critical for the efficient migration of neuroblasts to their destination. We further show that Fyn and Dab1 (disabled-1) decrease the cell-cell adhesion between chain-forming neuroblasts, which involves adherens junction-like structures. Our results suggest that Fyn-mediated regulation of the cell-cell adhesion of neuroblasts is critical for their detachment from chains in the postnatal brain.


Asunto(s)
Encéfalo/fisiología , Células-Madre Neurales/fisiología , Proteínas Proto-Oncogénicas c-fyn/fisiología , Animales , Encéfalo/citología , Encéfalo/crecimiento & desarrollo , Cadherinas/genética , Cateninas/metabolismo , Adhesión Celular/fisiología , Movimiento Celular/genética , Femenino , Técnicas de Silenciamiento del Gen , Masculino , Ratones , Proteínas del Tejido Nervioso/genética , Bulbo Olfatorio/citología , Bulbo Olfatorio/crecimiento & desarrollo , Bulbo Olfatorio/fisiología
9.
J Med Genet ; 54(6): 371-380, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28289185

RESUMEN

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.


Asunto(s)
Cara/anomalías , Síndromes Orofaciodigitales/genética , Anomalías Múltiples/genética , Trastornos de la Motilidad Ciliar/genética , Encefalocele/genética , Femenino , Heterocigoto , Humanos , Masculino , Mutación/genética , Enfermedades Renales Poliquísticas/genética , Proteínas/genética , Retinitis Pigmentosa
11.
J Neurosci ; 35(31): 11153-68, 2015 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-26245976

RESUMEN

Directional beating of ependymal (E) cells' cilia in the walls of the ventricles in the brain is essential for proper CSF flow. E cells display two forms of planar cell polarity (PCP): rotational polarity of individual cilium and translational polarity (asymmetric positioning of cilia in the apical area). The orientation of individual E cells varies according to their location in the ventricular wall (location-specific PCP). It has been hypothesized that hydrodynamic forces on the apical surface of radial glia cells (RGCs), the embryonic precursors of E cells, could guide location-specific PCP in the ventricular epithelium. However, the detection mechanisms for these hydrodynamic forces have not been identified. Here, we show that the mechanosensory proteins polycystic kidney disease 1 (Pkd1) and Pkd2 are present in primary cilia of RGCs. Ablation of Pkd1 or Pkd2 in Nestin-Cre;Pkd1(flox/flox) or Nestin-Cre;Pkd2(flox/flox) mice, affected PCP development in RGCs and E cells. Early shear forces on the ventricular epithelium may activate Pkd1 and Pkd2 in primary cilia of RGCs to properly polarize RGCs and E cells. Consistently, Pkd1, Pkd2, or primary cilia on RGCs were required for the proper asymmetric localization of the PCP protein Vangl2 in E cells' apical area. Analyses of single- and double-heterozygous mutants for Pkd1 and/or Vangl2 suggest that these genes function in the same pathway to establish E cells' PCP. We conclude that Pkd1 and Pkd2 mechanosensory proteins contribute to the development of brain PCP and prevention of hydrocephalus. SIGNIFICANCE STATEMENT: This study identifies key molecules in the development of planar cell polarity (PCP) in the brain and prevention of hydrocephalus. Multiciliated ependymal (E) cells within the brain ventricular epithelium generate CSF flow through ciliary beating. E cells display location-specific PCP in the orientation and asymmetric positioning of their cilia. Defects in this PCP can result in hydrocephalus. Hydrodynamic forces on radial glial cells (RGCs), the embryonic progenitors of E cells, have been suggested to guide PCP. We show that the mechanosensory proteins Pkd1 and Pkd2 localize to primary cilia in RGCs, and their ablation disrupts the development of PCP in E cells. Early shear forces on RGCs may activate Pkd1 and Pkd2 in RGCs' primary cilia to properly orient E cells. This study identifies key molecules in the development of brain PCP and prevention of hydrocephalus.


Asunto(s)
Polaridad Celular/genética , Ventrículos Cerebrales/metabolismo , Cilios/metabolismo , Células Ependimogliales/metabolismo , Canales Catiónicos TRPP/genética , Animales , Epéndimo/citología , Epéndimo/metabolismo , Células Ependimogliales/citología , Ratones , Ratones Noqueados , Canales Catiónicos TRPP/metabolismo
12.
J Appl Toxicol ; 35(7): 737-51, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25256750

RESUMEN

Ochratoxin A (OTA), a mycotoxin that was discovered as a secondary metabolite of the fungal species Aspergillus and Penicillium, is a common contaminant in food and animal feed. This mycotoxin has been described as teratogenic, carcinogenic, genotoxic, immunotoxic and has been proven a potent neurotoxin. Other authors have previously reported the effects of OTA in different structures of the central nervous system as well as in some neurogenic regions. However, the impact of OTA exposure in the subventricular zone (SVZ) has not been assessed yet. To elucidate whether OTA affects neural precursors of the mouse SVZ we investigated, in vitro and in vivo, the effects of OTA exposure on the SVZ and on the neural precursors obtained from this neurogenic niche. In this work, we prove the cumulative effect of OTA exposure on proliferation, differentiation and depletion of neural stem cells cultured from the SVZ. In addition, we corroborated these results in vivo by immunohistochemistry and electron microscopy. As a result, we found a significant alteration in the proliferation process, which was evidenced by a decrease in the number of 5-bromo-2-deoxyuridine-positive cells and glial cells, as well as, a significant decrease in the number of neuroblasts in the SVZ. To summarize, in this study we demonstrate how OTA could be a threat to the developing and the adult SVZ through its impact in cell viability, proliferation and differentiation in a dose-dependent manner.


Asunto(s)
Ventrículos Laterales/efectos de los fármacos , Micotoxinas/toxicidad , Ocratoxinas/toxicidad , Animales , Astrocitos/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ventrículos Laterales/patología , Ventrículos Laterales/ultraestructura , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Electrónica , Células-Madre Neurales/efectos de los fármacos , Neuroglía/efectos de los fármacos
13.
Neuron ; 112(4): 574-592.e10, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38086370

RESUMEN

The human amygdala paralaminar nucleus (PL) contains many immature excitatory neurons that undergo prolonged maturation from birth to adulthood. We describe a previously unidentified homologous PL region in mice that contains immature excitatory neurons and has previously been considered part of the amygdala intercalated cell clusters or ventral endopiriform cortex. Mouse PL neurons are born embryonically, not from postnatal neurogenesis, despite a subset retaining immature molecular and morphological features in adults. During juvenile-adolescent ages (P21-P35), the majority of PL neurons undergo molecular, structural, and physiological maturation, and a subset of excitatory PL neurons migrate into the adjacent endopiriform cortex. Alongside these changes, PL neurons develop responses to aversive and appetitive olfactory stimuli. The presence of this homologous region in both humans and mice points to the significance of this conserved mechanism of neuronal maturation and migration during adolescence, a key time period for amygdala circuit maturation and related behavioral changes.


Asunto(s)
Complejo Nuclear Basolateral , Células-Madre Neurales , Adolescente , Humanos , Adulto , Animales , Ratones , Neuronas , Amígdala del Cerebelo , Afecto
14.
EMBO Mol Med ; 16(6): 1228-1253, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38789599

RESUMEN

In the injured brain, new neurons produced from endogenous neural stem cells form chains and migrate to injured areas and contribute to the regeneration of lost neurons. However, this endogenous regenerative capacity of the brain has not yet been leveraged for the treatment of brain injury. Here, we show that in healthy brain chains of migrating new neurons maintain unexpectedly large non-adherent areas between neighboring cells, allowing for efficient migration. In instances of brain injury, neuraminidase reduces polysialic acid levels, which negatively regulates adhesion, leading to increased cell-cell adhesion and reduced migration efficiency. The administration of zanamivir, a neuraminidase inhibitor used for influenza treatment, promotes neuronal migration toward damaged regions, fosters neuronal regeneration, and facilitates functional recovery. Together, these findings shed light on a new mechanism governing efficient neuronal migration in the adult brain under physiological conditions, pinpoint the disruption of this mechanism during brain injury, and propose a promising therapeutic avenue for brain injury through drug repositioning.


Asunto(s)
Encéfalo , Movimiento Celular , Neuraminidasa , Neuronas , Neuraminidasa/metabolismo , Neuraminidasa/antagonistas & inhibidores , Movimiento Celular/efectos de los fármacos , Animales , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratones , Zanamivir/farmacología , Inhibidores Enzimáticos/farmacología , Ácidos Siálicos/metabolismo , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Recuperación de la Función/efectos de los fármacos , Ratones Endogámicos C57BL , Adhesión Celular/efectos de los fármacos , Humanos , Masculino
15.
Nat Commun ; 15(1): 1877, 2024 Mar 09.
Artículo en Inglés | MEDLINE | ID: mdl-38461182

RESUMEN

Axonal growth cones mediate axonal guidance and growth regulation. We show that migrating neurons in mice possess a growth cone at the tip of their leading process, similar to that of axons, in terms of the cytoskeletal dynamics and functional responsivity through protein tyrosine phosphatase receptor type sigma (PTPσ). Migrating-neuron growth cones respond to chondroitin sulfate (CS) through PTPσ and collapse, which leads to inhibition of neuronal migration. In the presence of CS, the growth cones can revert to their extended morphology when their leading filopodia interact with heparan sulfate (HS), thus re-enabling neuronal migration. Implantation of an HS-containing biomaterial in the CS-rich injured cortex promotes the extension of the growth cone and improve the migration and regeneration of neurons, thereby enabling functional recovery. Thus, the growth cone of migrating neurons is responsive to extracellular environments and acts as a primary regulator of neuronal migration.


Asunto(s)
Conos de Crecimiento , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores , Ratones , Animales , Conos de Crecimiento/metabolismo , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/metabolismo , Neurogénesis , Axones/metabolismo , Sulfatos de Condroitina/metabolismo , Encéfalo/metabolismo , Células Cultivadas
16.
Chemistry ; 19(40): 13538-46, 2013 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-23943097

RESUMEN

A simple and straightforward method for the orthogonal functionalisation of upconverting NaYF4 nanocrystals (UCNCs)-doped withYb(3+) and Er(3+)-based on N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide/N-hydroxysuccinimide (EDC/NHS) selective reactions between two dyes and two different reactive groups present at the periphery of the upconverting nanocrystals is reported. Organic-soluble UCNCs of 10 and 50 nm in size are encapsulated efficiently in a 1:1 mixture of two commercial 3000 Da poly(ethylene glycol) derivatives with two different reactive groups (amino and carboxylic groups). The water-dispersible UCNCs are non-cytotoxic, stable in the physiological environment, and present free amine and carboxylic reactive groups on their periphery, allowing rapid, selective, and modular covalent conjugation to payloads through EDC/NHS reactions. PEG-encapsulated UCNCs with and without covalent conjugation to payloads are characterised in vitro through spectroscopic, dynamic light scattering, and electron microscopy measurements. Living cell analyses coupled with TEM measurements confirm the uptake and low cytotoxicity of the coated UCNCs. They are linked covalently to two different dyes, internalised by living cells, and analysed by confocal microscopy. The related colocalisation measurements prove the reactivity of both amines and carboxylic acids on the periphery of the nanocrystals. This approach demonstrates that it is possible to produce water-dispersible and cyto-compatible dual-functional UCNCs.


Asunto(s)
Fluoruros/química , Nanopartículas/química , Polietilenglicoles/química , Succinimidas/química , Itrio/química , Estructura Molecular
17.
Front Neurosci ; 17: 1125999, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36908795

RESUMEN

In adult lizards, new neurons are generated from neural stem cells in the ventricular zone of the lateral ventricles. These new neurons migrate and integrate into the main telencephalic subdivisions. In this work we have studied adult neurogenesis in the lizard Podarcis liolepis (formerly Podarcis hispanica) by administering [3H]-thymidine and bromodeoxyuridine as proliferation markers and euthanizing the animals at different survival times to determine the identity of progenitor cells and to study their lineage derivatives. After short survival times, only type B cells are labeled, suggesting that they are neural stem cells. Three days after administration, some type A cells are labeled, corresponding to recently formed neuroblasts. Type A cells migrate to their final destinations, where they differentiate into mature neurons and integrate into functional circuits. Our results after long survival periods suggest that, in addition to actively dividing type B cells, there is also a type B subpopulation with low proliferative activity. We also found that new neurons incorporated into the olfactory bulb are generated both in situ, in the walls of the anterior extension of the lateral ventricle of the olfactory bulbs, but also at more caudal levels, most likely in anterior levels of the sulcus ventralis/terminalis. These cells follow a tangential migration toward the olfactory bulbs where they integrate. We hypothesized that at least part of the newly generated neurons would undergo a specialization process over time. In support of this prediction, we found two neuronal populations in the cellular layer of the medial cortex, which we named type I and II neurons. At intermediate survival times (1 month) only type II neurons were labeled with [3H]-thymidine, while at longer survival times (3, 6, or 12 months) both type I and type II neurons were labeled. This study sheds light on the ultrastructural characteristics of the ventricular zone of P. liolepis as a neurogenic niche, and adds to our knowledge of the processes whereby newly generated neurons in the adult brain migrate and integrate into their final destinations.

18.
Exp Neurol ; 365: 114412, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37075967

RESUMEN

Normal pressure hydrocephalus (NPH) compromises the morphology of the corpus callosum (CC). This study aims to determine whether 60- or 120-day NPH disrupts the cytoarchitecture and functioning of white matter (WM) and oligodendrocyte precursor cells (OPCs) and establish whether these changes are reversible after hydrocephalus treatment. NPH was induced in CD1 adult mice by inserting an obstructive lamina in the atrium of the aqueduct of Sylvius. Five groups were assembled: sham-operated controls (60 and 120 days), NPH groups (60 and 120 days), and the hydrocephalus-treated group (obstruction removal after 60-d hydrocephalus). We analyzed the cellular integrity of the CC by immunohistochemistry, TUNEL analysis, Western blot assays, and transmission electron microscopy (TEM). We found a reduction in the width of the CC at 60 and 120 days of NPH. TEM analysis demonstrated myelin abnormalities, degenerative changes in the WM, and an increase in the number of hyperdense (dark) axons that were associated with significant astrogliosis, and microglial reactivity. Hydrocephalus also caused a decrease in the expression of myelin-related proteins (MOG and CNPase) and reduced proliferation and population of OPCs, resulting in fewer mature oligodendrocytes. Hydrocephalus resolution only recovers the OPC proliferation and MOG protein density, but the rest of the WM abnormalities persisted. Interestingly, all these cellular and molecular anomalies occur in the absence of behavioral changes. The results suggest that NPH severely disrupts the myelin integrity and affects the OPC turnover in the CC. Remarkably, most of these deleterious events persist after hydrocephalus treatment, which suggests that a late treatment conveys irreversible changes in the WM of CC.


Asunto(s)
Hidrocéfalo Normotenso , Células Precursoras de Oligodendrocitos , Ratones , Animales , Cuerpo Calloso , 2',3'-Nucleótido Cíclico Fosfodiesterasas/genética , Vaina de Mielina , Oligodendroglía , Proteínas de la Mielina , Proliferación Celular
19.
Biomaterials ; 294: 122003, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36736095

RESUMEN

The mammalian brain has very limited ability to regenerate lost neurons and recover function after injury. Promoting the migration of young neurons (neuroblasts) derived from endogenous neural stem cells using biomaterials is a new and promising approach to aid recovery of the brain after injury. However, the delivery of sufficient neuroblasts to distant injured sites is a major challenge because of the limited number of scaffold cells that are available to guide neuroblast migration. To address this issue, we have developed an amphiphilic peptide [(RADA)3-(RADG)] (mRADA)-tagged N-cadherin extracellular domain (Ncad-mRADA), which can remain in mRADA hydrogels and be injected into deep brain tissue to facilitate neuroblast migration. Migrating neuroblasts directly contacted the fiber-like Ncad-mRADA hydrogel and efficiently migrated toward an injured site in the striatum, a deep brain area. Furthermore, application of Ncad-mRADA to neonatal cortical brain injury efficiently promoted neuronal regeneration and functional recovery. These results demonstrate that self-assembling Ncad-mRADA peptides mimic both the function and structure of endogenous scaffold cells and provide a novel strategy for regenerative therapy.


Asunto(s)
Cadherinas , Células-Madre Neurales , Animales , Encéfalo , Neuronas , Péptidos , Mamíferos
20.
Elife ; 122023 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-36790165

RESUMEN

Centrosomes are orbited by centriolar satellites, dynamic multiprotein assemblies nucleated by Pericentriolar material 1 (PCM1). To study the requirement for centriolar satellites, we generated mice lacking PCM1, a crucial component of satellites. Pcm1-/- mice display partially penetrant perinatal lethality with survivors exhibiting hydrocephalus, oligospermia, and cerebellar hypoplasia, and variably expressive phenotypes such as hydronephrosis. As many of these phenotypes have been observed in human ciliopathies and satellites are implicated in cilia biology, we investigated whether cilia were affected. PCM1 was dispensable for ciliogenesis in many cell types, whereas Pcm1-/- multiciliated ependymal cells and human PCM1-/- retinal pigmented epithelial 1 (RPE1) cells showed reduced ciliogenesis. PCM1-/- RPE1 cells displayed reduced docking of the mother centriole to the ciliary vesicle and removal of CP110 and CEP97 from the distal mother centriole, indicating compromised early ciliogenesis. Similarly, Pcm1-/- ependymal cells exhibited reduced removal of CP110 from basal bodies in vivo. We propose that PCM1 and centriolar satellites facilitate efficient trafficking of proteins to and from centrioles, including the departure of CP110 and CEP97 to initiate ciliogenesis, and that the threshold to trigger ciliogenesis differs between cell types.


Asunto(s)
Centriolos , Cilios , Animales , Femenino , Humanos , Ratones , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Centriolos/metabolismo , Centrosoma/metabolismo , Cilios/metabolismo , Proteínas del Citoesqueleto/metabolismo
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