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1.
Nat Aging ; 3(4): 380-390, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37117787

RESUMEN

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian hippocampus1. Advancing age leads to a decline in neurogenesis, which is associated with impaired cognition2,3. The cellular mechanisms causing reduced neurogenesis with advancing age remain largely unknown. We genetically labeled NSCs through conditional recombination driven by the regulatory elements of the stem-cell-expressed gene GLI family zinc finger 1 (Gli1) and used chronic intravital imaging to follow individual NSCs and their daughter cells over months within their hippocampal niche4,5. We show that aging affects multiple steps, from cell cycle entry of quiescent NSCs to determination of the number of surviving cells, ultimately causing reduced clonal output of individual NSCs. Thus, we here define the developmental stages that may be targeted to enhance neurogenesis with the aim of maintaining hippocampal plasticity with advancing age.


Asunto(s)
Disfunción Cognitiva , Células-Madre Neurales , Ratones , Animales , Neuronas/metabolismo , Neurogénesis/fisiología , Hipocampo , Disfunción Cognitiva/metabolismo , Mamíferos
2.
Proc Natl Acad Sci U S A ; 118(28)2021 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-34244440

RESUMEN

Oligodendrocyte precursor cells (OPCs) retain the capacity to remyelinate axons in the corpus callosum (CC) upon demyelination. However, the dynamics of OPC activation, mode of cell division, migration, and differentiation on a single-cell level remain poorly understood due to the lack of longitudinal observations of individual cells within the injured brain. After inducing focal demyelination with lysophosphatidylcholin in the CC of adult mice, we used two-photon microscopy to follow for up to 2 mo OPCs and their differentiating progeny, genetically labeled through conditional recombination driven by the regulatory elements of the gene Achaete-scute homolog 1. OPCs underwent several rounds of symmetric and asymmetric cell divisions, producing a subset of daughter cells that differentiates into myelinating oligodendrocytes. While OPCs continue to proliferate, differentiation into myelinating oligodendrocytes declines with time, and death of OPC-derived daughter cells increases. Thus, chronic in vivo imaging delineates the cellular principles leading to remyelination in the adult brain, providing a framework for the development of strategies to enhance endogenous brain repair in acute and chronic demyelinating disease.


Asunto(s)
Envejecimiento/fisiología , Cuerpo Calloso/diagnóstico por imagen , Imagenología Tridimensional , Remielinización/fisiología , Animales , Muerte Celular , División Celular , Movimiento Celular , Células Clonales , Ratones , Células Precursoras de Oligodendrocitos/citología
3.
Cell Stem Cell ; 28(5): 967-977.e8, 2021 05 06.
Artículo en Inglés | MEDLINE | ID: mdl-33631115

RESUMEN

Neural stem cells (NSCs) generate neurons throughout life in the hippocampal dentate gyrus. With advancing age, levels of neurogenesis sharply drop, which has been associated with a decline in hippocampal memory function. However, cell-intrinsic mechanisms mediating age-related changes in NSC activity remain largely unknown. Here, we show that the nuclear lamina protein lamin B1 (LB1) is downregulated with age in mouse hippocampal NSCs, whereas protein levels of SUN-domain containing protein 1 (SUN1), previously implicated in Hutchinson-Gilford progeria syndrome (HGPS), increase. Balancing the levels of LB1 and SUN1 in aged NSCs restores the strength of the endoplasmic reticulum diffusion barrier that is associated with segregation of aging factors in proliferating NSCs. Virus-based restoration of LB1 expression in aged NSCs enhances stem cell activity in vitro and increases progenitor cell proliferation and neurogenesis in vivo. Thus, we here identify a mechanism that mediates age-related decline of neurogenesis in the mammalian hippocampus.


Asunto(s)
Envejecimiento , Lamina Tipo B , Células-Madre Neurales , Progeria , Animales , Hipocampo/citología , Ratones , Neurogénesis
4.
Nat Neurosci ; 24(2): 225-233, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33349709

RESUMEN

Neural stem cells (NSCs) generate neurons throughout life in the mammalian hippocampus. However, the potential for long-term self-renewal of individual NSCs within the adult brain remains unclear. We used two-photon microscopy and followed NSCs that were genetically labeled through conditional recombination driven by the regulatory elements of the stem cell-expressed genes GLI family zinc finger 1 (Gli1) or achaete-scute homolog 1 (Ascl1). Through intravital imaging of NSCs and their progeny, we identify a population of Gli1-targeted NSCs showing long-term self-renewal in the adult hippocampus. In contrast, once activated, Ascl1-targeted NSCs undergo limited proliferative activity before they become exhausted. Using single-cell RNA sequencing, we show that Gli1- and Ascl1-targeted cells have highly similar yet distinct transcriptional profiles, supporting the existence of heterogeneous NSC populations with diverse behavioral properties. Thus, we here identify long-term self-renewing NSCs that contribute to the generation of new neurons in the adult hippocampus.


Asunto(s)
Hipocampo/crecimiento & desarrollo , Células-Madre Neurales/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Linaje de la Célula , Femenino , Perfilación de la Expresión Génica , Hipocampo/citología , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/genética , Microscopía Intravital , Masculino , Metalotioneína 3 , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía de Fluorescencia por Excitación Multifotónica , Regeneración Nerviosa , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Análisis de la Célula Individual , Proteína con Dedos de Zinc GLI1/biosíntesis , Proteína con Dedos de Zinc GLI1/genética
5.
Glia ; 66(9): 1929-1946, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29732603

RESUMEN

Sox2 is a transcription factor active in the nervous system, within different cell types, ranging from radial glia neural stem cells to a few specific types of differentiated glia and neurons. Mutations in the human SOX2 transcription factor gene cause various central nervous system (CNS) abnormalities, involving hippocampus and eye defects, as well as ataxia. Conditional Sox2 mutation in mouse, with different Cre transgenes, previously recapitulated different essential features of the disease, such as hippocampus and eye defects. In the cerebellum, Sox2 is active from early embryogenesis in the neural progenitors of the cerebellar primordium; Sox2 expression is maintained, postnatally, within Bergmann glia (BG), a differentiated cell type essential for Purkinje neurons functionality and correct motor control. By performing Sox2 Cre-mediated ablation in the developing and postnatal mouse cerebellum, we reproduced ataxia features. Embryonic Sox2 deletion (with Wnt1Cre) leads to reduction of the cerebellar vermis, known to be commonly related to ataxia, preceded by deregulation of Otx2 and Gbx2, critical regulators of vermis development. Postnatally, BG is progressively disorganized, mislocalized, and reduced in mutants. Sox2 postnatal deletion, specifically induced in glia (with GLAST-CreERT2), reproduces the BG defect, and causes (milder) ataxic features. Our results define a role for Sox2 in cerebellar function and development, and identify a functional requirement for Sox2 within postnatal BG, of potential relevance for ataxia in mouse mutants, and in human patients.


Asunto(s)
Ataxia/metabolismo , Vermis Cerebeloso/crecimiento & desarrollo , Vermis Cerebeloso/metabolismo , Neuroglía/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Animales Recién Nacidos , Ataxia/patología , Células Cultivadas , Vermis Cerebeloso/patología , Regulación de la Expresión Génica/fisiología , Ácido Glutámico/metabolismo , Proteínas de Homeodominio/metabolismo , Ratones Transgénicos , Mutación , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neuroglía/patología , Factores de Transcripción Otx/metabolismo , Factores de Transcripción SOXB1/genética , Transmisión Sináptica/fisiología
6.
Science ; 359(6376): 658-662, 2018 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-29439238

RESUMEN

Neural stem and progenitor cells (NSPCs) generate neurons throughout life in the mammalian hippocampus. We used chronic in vivo imaging and followed genetically labeled individual NSPCs and their progeny in the mouse hippocampus for up to 2 months. We show that NSPCs targeted by the endogenous Achaete-scute homolog 1 (Ascl1) promoter undergo limited rounds of symmetric and asymmetric divisions, eliciting a burst of neurogenic activity, after which they are lost. Further, our data reveal unexpected asymmetric divisions of nonradial glia-like NSPCs. Cell fates of Ascl1-labeled lineages suggest a developmental-like program involving a sequential transition from a proliferative to a neurogenic phase. By providing a comprehensive description of lineage relationships, from dividing NSPCs to newborn neurons integrating into the hippocampal circuitry, our data offer insight into how NSPCs support life-long hippocampal neurogenesis.


Asunto(s)
División Celular , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Células-Madre Neurales/citología , Neurogénesis , Neuroimagen , Neuronas/citología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Muerte Celular , División Celular/genética , Ratones , Red Nerviosa/citología , Red Nerviosa/crecimiento & desarrollo , Neurogénesis/genética , Neuroglía/citología , Regiones Promotoras Genéticas
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