PSmad3+/Olig2- expression defines a subpopulation of gfap-GFP+/Sox9+ neural progenitors and radial glia-like cells in mouse dentate gyrus through embryonic and postnatal development.

In mouse dentate gyrus, radial glia-like cells (RGLs) persist throughout life and play a critical role in the generation of granule neurons. A large body of evidence has shown that the combinatorial expression of transcription factors (TFs) defines cell types in the developing central nervous system (CNS). As yet, the identification of specific TFs that exclusively define RGLs in the developing mouse dentate gyrus (DG) remains elusive. Here we show that phospho-Smad3 (PSmad3) is expressed in a subpopulation of neural progenitors in the DG. During embryonic stage (E14-15), PSmad3 was predominantly expressed in gfap-GFP-positive (GFP+)/Sox2+ progenitors located at the lower dentate notch (LDN). As the development proceeds (E16-17), the vast majority of PSmad3+ cells were GFP+/Sox2+/Prox1low+/Ki67+ proliferative progenitors that eventually differentiated into granule neurons. During postnatal stage (P1-P6) PSmad3 expression was observed in GFP+ progenitors and astrocytes. Subsequently, at P14-P60, PSmad3 expression was found both in GFP+ RGLs in the subgranular zone (SGZ) and astrocytes in the molecular layer (ML) and hilus. Notably, PSmad3+ SGZ cells did not express proliferation markers such as PCNA and phospho-vimentin, suggesting that they are predominantly quiescent from P14 onwards. Significantly PSmad3+/GFP+ astrocytes, but not SGZ cells, co-expressed Olig2 and S100ß. Together, PSmad3+/Olig2- expression serves as an exclusive marker for a specific subpopulation of GFP+ neural progenitors and RGLs in the mouse DG during both embryonic and postnatal period.

Radial glia and radial glia-like cells: Their role in neurogenesis and regeneration.

Radial glia is a cell type traditionally associated with the developing nervous system, particularly with the formation of cortical layers in the mammalian brain. Nonetheless, some of these cells, or closely related types, called radial glia-like cells are found in adult central nervous system structures, functioning as neurogenic progenitors in normal homeostatic maintenance and in response to injury. The heterogeneity of radial glia-like cells is nowadays being probed with molecular tools, primarily by the expression of specific genes that define cell types. Similar markers have identified radial glia-like cells in the nervous system of non-vertebrate organisms. In this review, we focus on adult radial glia-like cells in neurogenic processes during homeostasis and in response to injury. We highlight our results using a non-vertebrate model system, the echinoderm Holothuria glaberrima where we have described a radial glia-like cell that plays a prominent role in the regeneration of the holothurian central nervous system.

Sepsis promotes gliogenesis and depletes the pool of radial glia like stem cells in the hippocampus.

Sepsis associated encephalopathy (SAE) is a major complication of patients surviving sepsis with a prevalence up to 70%. Although the initial pathophysiological events of SAE are considered to arise during the acute phase of sepsis, there is increasing evidence that SAE leads to persistent brain dysfunction with severe cognitive decline in later life. Previous studies suggest that the hippocampal formation is particularly involved leading to atrophy in later stages. Thereby, the underlying cellular mechanisms are only poorly understood. Here, we hypothesized that endogenous neural stems cells and adult neurogenesis in the hippocampus are impaired following sepsis and that these changes may contribute to persistent cognitive dysfunction when the animals have physically fully recovered. We used the murine sepsis model of peritoneal contamination and infection (PCI) and combined different labeling methods of precursor cells with confocal microscopy studies to assess the neurogenic niche in the dentate gyrus at day 42 postsepsis. We found that following sepsis i) gliogenesis is increased, ii) the absolute number of radial glia-like cells (type 1 cells), which are considered the putative stem cells, is significantly reduced, iii) the generation of new neurons is not significantly altered, while iv) the synaptic spine maturation of new neurons is impaired with a shift to expression of more immature and less mature spines. In conclusion, sepsis mainly leads to depletion of the neural stem cell pool and enhanced gliogenesis in the dentate gyrus which points towards an accelerated aging of the hippocampus due to septic insult.

Glycogen Synthase Kinase-3ß Regulates Equilibrium Between Neurogenesis and Gliogenesis in Rat Model of Parkinson's Disease: a Crosstalk with Wnt and Notch Signaling.

Neurogenesis involves generation of functional newborn neurons from neural stem cells (NSCs). Insufficient formation or accelerated degeneration of newborn neurons may contribute to the severity of motor/nonmotor symptoms of Parkinson's disease (PD). However, the functional role of adult neurogenesis in PD is yet not explored and whether glycogen synthase kinase-3ß (GSK-3ß) affects multiple steps of adult neurogenesis in PD is still unknown. We investigated the possible underlying molecular mechanism of impaired adult neurogenesis associated with PD. Herein, we show that single intra-medial forebrain bundle (MFB) injection of 6-hydroxydopamine (6-OHDA) efficiently induced long-term activation of GSK-3ß and reduced NSC self-renewal, proliferation, neuronal migration, and neuronal differentiation accompanied with increased astrogenesis in subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Indeed, 6-OHDA also delayed maturation of neuroblasts in the DG as witnessed by their reduced dendritic length and arborization. Using a pharmacological approach to inhibit GSK-3ß activation by specific inhibitor SB216763, we show that GSK-3ß inhibition enhances radial glial cells, NSC proliferation, self-renewal in the SVZ, and the subgranular zone (SGZ) in the rat PD model. Pharmacological inhibition of GSK-3ß activity enhances neuroblast population in SVZ and SGZ and promotes migration of neuroblasts towards the rostral migratory stream and lesioned striatum from dorsal SVZ and lateral SVZ, respectively, in PD model. GSK-3ß inhibition enhances dendritic arborization and survival of granular neurons and stimulates NSC differentiation towards the neuronal phenotype in DG of PD model. The aforementioned effects of GSK-3ß involve a crosstalk between Wnt/ß-catenin and Notch signaling pathways that are known to regulate NSC dynamics.

Roof Plate-Derived Radial Glial-like Cells Support Developmental Growth of Rapidly Adapting Mechanoreceptor Ascending Axons.

Spinal cord longitudinal axons comprise some of the longest axons in our body. However, mechanisms that drive this extra long-distance axonal growth are largely unclear. We found that ascending axons of rapidly adapting (RA) mechanoreceptors closely abut a previously undescribed population of roof plate-derived radial glial-like cells (RGLCs) in the spinal cord dorsal column, which form a network of processes enriched with growth-promoting factors. In dreher mutant mice that lack RGLCs, the lengths of ascending RA mechanoreceptor axon branches are specifically reduced, whereas their descending and collateral branches, and other dorsal column and sensory pathways, are largely unaffected. Because the number and intrinsic growth ability of RA mechanoreceptors are normal in dreher mice, our data suggest that RGLCs provide critical non-cell autonomous growth support for the ascending axons of RA mechanoreceptors. Together, our work identifies a developmental mechanism specifically required for long-range spinal cord longitudinal axons.

p38α controls self-renewal and fate decision of neurosphere-forming cells in adult hippocampus.

Neural stem cells (NSC) from the adult hippocampus easily lose their activity in vitro. Efficient in vitro expansion of adult hippocampus-derived NSC is important for generation of tools for research and cell therapy. Here, we show that a single copy disruption or pharmacological inhibition of p38α enables successful long-term neurosphere culture of adult mouse hippocampal cells. Expanded neurospheres with high proliferative activity differentiated into the three neuronal lineages under differentiating conditions. Thus, inhibition of p38α can maintain adult hippocampal NSC activity in vitro.

A developmental perspective on adult hippocampal neurogenesis.

The generation of new neurons from neural stem cells (NSCs) throughout adult life in the mammalian brain is a biological process that fascinates scientists for its uniqueness and restorative potential. In the dentate gyrus (DG) of the hippocampus NSCs are able to self-renew and generate new granule cells and astrocytes through a complex and plastic mechanism that can be regulated by endogenous and exogenous cues at different levels. Unexpected recent findings suggest that the population of NSCs is heterogeneous in morphology and behavior. We herein explore the hypothesis that NSC heterogeneity and the neurogenic potential of the DG depends on their developmental origin. We provide an up-to-date picture of the process of neurogenesis in the adult hippocampus with an especial focus on NSCs and outline key unsolved aspects. Further, we discuss the origin of NSCs in the adult DG from a developmental perspective and explore the possibility of NSC heterogeneity being determined from early postnatal periods and being responsible for the neurogenic output of the DG in the long term.