RESUMEN
Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression.
Asunto(s)
Células-Madre Neurales , Ratones , Animales , Células-Madre Neurales/metabolismo , Aprendizaje Espacial , Factor D de Crecimiento Endotelial Vascular/metabolismo , Proliferación Celular/fisiología , Hipocampo/metabolismo , Neurogénesis/genética , Ratones Noqueados , Péptidos y Proteínas de Señalización Intercelular/metabolismoRESUMEN
Autism spectrum disorder (ASD) comprises a group of multifactorial neurodevelopmental disorders primarily characterized by deficits in social interaction and repetitive behavior. Although the onset is typically in early childhood, ASD poses a lifelong challenge for both patients and caretakers. Adult neurogenesis (AN) is the process by which new functional neurons are created from neural stem cells existing in the post-natal brain. The entire event is based on a sequence of cellular processes, such as proliferation, specification of cell fate, maturation, and ultimately, synaptic integration into the existing neural circuits. Hence, AN is implicated in structural and functional brain plasticity throughout life. Accumulating evidence shows that impaired AN may underlie some of the abnormal behavioral phenotypes seen in ASD. In this review, we approach the interconnections between the molecular pathways related to AN and ASD. We also discuss existing therapeutic approaches targeting such pathways both in preclinical and clinical studies. A deeper understanding of how ASD and AN reciprocally affect one another could reveal important converging pathways leading to the emergence of psychiatric disorders.
Asunto(s)
Trastorno del Espectro Autista/patología , Neurogénesis/fisiología , Adulto , Animales , Trastorno del Espectro Autista/genética , Preescolar , Humanos , Células-Madre Neurales , Trastornos del Neurodesarrollo , Neurogénesis/genéticaRESUMEN
Aging causes many changes in the human body, and is a high risk for various diseases. Dementia, a common age-related disease, is a clinical disorder triggered by neurodegeneration. Brain damage caused by neuronal death leads to cognitive decline, memory loss, learning inabilities and mood changes. Numerous disease conditions may cause dementia; however, the most common one is Alzheimer's disease (AD), a futile and yet untreatable illness. Adult neurogenesis carries the potential of brain self-repair by an endogenous formation of newly-born neurons in the adult brain; however it also declines with age. Strategies to improve the symptoms of aging and age-related diseases have included different means to stimulate neurogenesis, both pharmacologically and naturally. Finally, the regulatory mechanisms of stem cells neurogenesis or a functional integration of newborn neurons have been explored to provide the basis for grafted stem cell therapy. This review aims to provide an overview of AD pathology of different neural and glial cell types and summarizes current strategies of experimental stem cell treatments and their putative future use in clinical settings.
Asunto(s)
Enfermedad de Alzheimer/terapia , Neurogénesis , Trasplante de Células Madre , Enfermedad de Alzheimer/patología , Animales , Humanos , Neuroglía/patología , Neuronas/patología , Trasplante de Células Madre/métodosRESUMEN
Increasing evidence demonstrates the importance of hippocampal neurogenesis, a fundamental mechanism of neuroplasticity associated with cognition and emotion, in correlation to neurodegenerative and psychiatric disorders. Neuropsychiatric disorders are often a result of chronic stress or pain followed by inflammation; all these conditions manifest cognitive deficits and impairments in neurogenesis. However, while some individuals are more susceptible to stress, others are able to adapt to new environments via mechanisms of resilience. In light of this emerging field and based on extensive research, the role of neurogenesis is summarized and presented as a potentially powerful therapeutic tool.
Asunto(s)
Hipocampo/fisiopatología , Inflamación/fisiopatología , Neurogénesis , Dolor/fisiopatología , Cognición/fisiología , Trastornos del Conocimiento/fisiopatología , Emociones/fisiología , Humanos , Modelos NeurológicosRESUMEN
Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal function.
Asunto(s)
Antioxidantes , Cuerpo Estriado , Estrés Oxidativo , Animales , Ratones , Antioxidantes/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas del Ojo/metabolismo , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/metabolismo , Neuronas/metabolismo , Oxidación-Reducción , Estrés Oxidativo/fisiología , Cuerpo Estriado/fisiologíaRESUMEN
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems.
Asunto(s)
Trastorno del Espectro Autista/patología , Redes Reguladoras de Genes , Transducción de Señal , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Mutación , Serina-Treonina Quinasas TOR/metabolismo , Proteínas ras/metabolismoRESUMEN
Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing, pathogen removal, and autoimmunity. We showed that patients with multiple sclerosis (MS) have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis (EAE). However, unexpectedly, progranulin-deficient mice (Grn-/-) were resistant to EAE, and this resistance was fully restored by wild-type bone marrow transplantation. FACS analyses revealed a loss of MHC-II-positive antigen-presenting cells in Grn-/- mice and a reduction in the number of CD8+ and CD4+ T-cells along with a strong increase in the number of scavenger receptor class B (CD36+) phagocytes, suggesting defects in antigen presentation along with a compensatory increase in phagocytosis. Indeed, bone marrow-derived dendritic cells from Grn-/- mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation. An increase in the number of CD36+ phagocytes was associated with increased local inflammation at the site of immunization, stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes, an increase in the phagocytosis of E. coli particles and latex beads and defects in the clearance of the material. Hence, the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation, and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
Asunto(s)
Resistencia a la Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Progranulinas/deficiencia , Adolescente , Adulto , Animales , Células Presentadoras de Antígenos/inmunología , Antígenos/metabolismo , Médula Ósea/patología , Trasplante de Médula Ósea , Células Dendríticas/metabolismo , Encefalomielitis Autoinmune Experimental/sangre , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Recuento de Linfocitos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/patología , Células Mieloides/patología , Ovalbúmina , Fagocitos/metabolismo , Fagocitosis , Progranulinas/sangre , Progranulinas/metabolismo , Receptores Depuradores de Clase B/metabolismo , Linfocitos T/inmunología , Adulto JovenRESUMEN
Adult neural stem cells reside in a specialized niche in the subventricular zone (SVZ). Throughout life they give rise to adult-born neurons in the olfactory bulb (OB), thus contributing to neural plasticity and pattern discrimination. Here, we show that the neurovascular protein EGFL7 is secreted by endothelial cells and neural stem cells (NSCs) of the SVZ to shape the vascular stem-cell niche. Loss of EGFL7 causes an accumulation of activated NSCs, which display enhanced activity and re-entry into the cell cycle. EGFL7 pushes activated NSCs towards quiescence and neuronal progeny towards differentiation. This is achieved by promoting Dll4-induced Notch signalling at the blood vessel-stem cell interface. Fewer inhibitory neurons form in the OB of EGFL7-knockout mice, which increases the absolute signal conducted from the mitral cell layer of the OB but decreases neuronal network synchronicity. Consequently, EGFL7-knockout mice display severe physiological defects in olfactory behaviour and perception.
Asunto(s)
Células Madre Adultas/metabolismo , Ventrículos Laterales/metabolismo , Neurogénesis , Percepción Olfatoria , Proteínas/metabolismo , Células Madre Adultas/citología , Animales , Proteínas de Unión al Calcio , Ciclo Celular , Familia de Proteínas EGF , Ventrículos Laterales/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células-Madre Neurales/citología , Células-Madre Neurales/metabolismo , Plasticidad Neuronal , Proteínas/genética , Transducción de SeñalRESUMEN
BACKGROUND: Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. RESULTS: Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice. CONCLUSION: We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.