Estructura nuclear y quiescencia en células madre neurales

La zona subventricular-ventricular (ZSV-V) es un extenso nicho neurogénico que contiene células madre neurales (astrocitos B) en las paredes de los ventrículos laterales del cerebro adulto de mamíferos. Las células del subtipo B1 han sido identificadas clásicamente como las verdaderas células madre, tienen un origen embrionario y se mantienen quiescentes hasta que se reactivan post-natalmente. En el presente estudio, mostramos que una subpoblación de células B de la ZSV-V presenta una estructura nuclear denominada “lámina de cromatina de la envoltura nuclear” (ELCS, del inglés envelope-limited chromatin sheets), previamente descrita en células normales y cancerosas. Esta estructura se caracteriza por presentar una lámina de heterocromatina de 30 nm limitada en ambos lados por las membranas nucleares interna y externa. A través de marcadores moleculares, estudios de proliferación con 3H-Timidina y la administración de la droga antimitótica Ara-C, encontramos que las células B1 con ELCS corresponden a células madre neurales quiescentes GFAP+, BLBP+, GLAST+, Nestina- y EGFR-. Además, los estudios de microscopía electrónica revelaron que las ELCS empiezan a formarse en las células de glía radial en los estadios embrionarios y se mantienen presentes durante las etapas postnatales tempranas en una subpoblación de células tipo B que disminuye drásticamente con la edad. Adicionalmente, las ELCS representan un compartimento nuclear que contiene modificaciones epigenéticas específicas y telómeros. Estas estructuras también se encuentran presentes en la zona subgranular del giro dentado de roedores y en la ZSV-V de primates no humanos y humanos. Estos resultados muestran que las células madre neurales quiescentes presentan un compartimento muy bien definido estructuralmente y molecularmente en su núcleo, característica que contribuirá a identificar estos progenitores primarios y estudiar como funciona su regulación génicaThe ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (B1 astrocytes) in the walls of the lateral ventricles of the adult brain. B1 cells have an embryonic origin and remain largely quiescent until they become reactivated postnatally. In this study, we show that a subset of adult V-SVZ B1 cells has nuclear envelope limited chromatin sheets or ELCS, previously described in other normal and cancer cells. Using molecular markers, 3H-thymidine birthdating and the antimitotic drug Ara-C, we found that type B1 cells with ELCS correspond to GFAP+, BLBP+, GLAST+, Nestin- and EGFR- quiescent neural stem cells. TEM reveals that nuclear ELCS begin forming in the embryo radial glia cells and remain during early postnatal stages in a subpopulation of type B cells that drastically decreases with age. Additionally, ELCS represent a specific nuclear compartment that contains specific epigenetic modifications and telomeres. Notably, we found that ELCS are a preserved nuclear structure in the subgranular zone of the rodent dentate gyrus and in the ZSV-V of nonhuman and human primate neural stem cells. These results reveal that quiescent neural stem cells have a unique structurally and molecularly defined compartment in their nuclei, a feature that may help to identify these primary progenitors and study their gene regulation

The generation of oligodendroglial cells is preserved in the rostral migratory stream during aging.

The subventricular zone (SVZ) is the largest source of newly generated cells in the adult mammalian brain. SVZ-derived neuroblasts migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate into mature neurons. Additionally, a small proportion of SVZ-derived cells contribute to the generation of myelinating oligodendrocytes. The production of new cells in the SVZ decreases during aging, affecting the incorporation of new neurons into the OB. However, the age-related changes that occur across the RMS are not fully understood. In this study we evaluate how aging affects the cellular organization of migrating neuroblast chains, the proliferation, and the fate of the newly generated cells in the SVZ-OB system. By using electron microscopy and immunostaining, we found that the RMS path becomes discontinuous and its cytoarchitecture is disorganized in aged mice (24-month-old mice). Subsequently, OB neurogenesis was impaired in the aged brain while the production of oligodendrocytes was not compromised. These findings provide new insight into oligodendrocyte preservation throughout life. Further exploration of this matter could help the development of new strategies to prevent neurological disorders associated with senescence

Unique Organization of the Nuclear Envelope in the Post-natal Quiescent Neural Stem Cells

Neural stem cells (B1 astrocytes; NSCs) in the adult ventricular-subventricular-zone (V-SVZ) originate in the embryo. Surprisingly, recent work has shown that B1 cells remain largely quiescent. They are reactivated postnatally to function as primary progenitors for neurons destined for the olfactory bulb and some corpus callosum oligodendrocytes. The cellular and molecular properties of quiescent B1 cells remain unknown. Here we found that a subpopulation of B1 cells has a unique nuclear envelope invagination specialization similar to envelope-limited chromatin sheets (ELCS), reported in certain lymphocytes and some cancer cells. Using molecular markers, [3H]thymidine birth-dating, and Ara-C, we found that B1 cells with ELCS correspond to quiescent NSCs. ELCS begin forming in embryonic radial glia cells and represent a specific nuclear compartment containing particular epigenetic modifications and telomeres. These results reveal a unique nuclear compartment in quiescent NSCs, which is useful for identifying these primary progenitors and study their gene regulation

Axonal Control of the Adult Neural Stem Cell Niche

SUMMARYThe ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSC) in the walls of the lateral ventricles of the adult brain. How the adult brain’s neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C

Axons take a dive: Specialized contacts of serotonergic axons with cells in the walls of the lateral ventricles in mice and humans.

In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular-subventricular zone (V-SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells

Axons take a dive: Specialized contacts of serotonergic axons with cells in the walls of the lateral ventricles in mice and humans.

In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular-subventricular zone (V-SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells

Axonal control of the adult neural stem cell niche

The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSCs) in the walls of the lateral ventricles of the adult brain. How the adult brain\u27s neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C

A cross-species proteomic map reveals neoteny of human synapse development

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood1,2. Here we generate a cross-species proteomic map of synapse development in the human, macaque and mouse neocortex. By tracking the changes of more than 1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we find that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that human PSDs mature about two to three times slower than those of other species and contain higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of RhoGEF signalling in human neurons delays morphological maturation of dendritic spines and functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell-type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation