Characterization of progenitor cells during the development of the ventral telencephalon of the mouse

During development of the mammalian telencephalon stem cells and more lineage restricted progenitor cells give rise to all cell types which later are contributing to this fascinatingly orchestrated organ. Initially, at the stage of neuroepithelial cells, these stem cells increase their pool by symmetric proliferative divisions and later, when matured to radial glia (RG) cells they give rise to neurons either directly, or indirectly via intermediate progenitors. At later stages of development, radial glia generate glial progenitor cells or differentiate to glial cells directly. How stem cells orchestrate this sequel of tissue genesis has been unraveled by pioneer studies focusing on stem cells of the murine cerebral neocortex. However, the ways how one of the biggest brain regions of the murine brain, the ventral telencephalon which later forms the basal ganglia, facilitates this process, have been largely unknown. Over the past years, increasing interest has been put forward in understanding how the human cortex and its dramatically expanded surface with gyri and sulci is build up on a cellular level during embryonic development. Studies both on embryonic human and primate brains revealed that an expanded germinal zone, the outer subventricular zone (OSVZ), seeded with a heterogeneous population of progenitor cells which are rare in lissencepahlic brains, is responsible to form this enormously elevated brain region. However, both human and primate material is rare and genetically modified models are not available. To investigate the cellular mechanisms taking place in an expanded mammalian brain region in the mouse would be of great interest technically and from an evolutionary perspective. Therefore, live-imaging studies of individual progenitor cells in embryonic brainslices which have been labeled in the lateral ganglionic eminence (LGE) by in-utero electroporation were carried out to reveal lineages emanating from single RG cells. The development of the ventral telencephalon precedes that of the dorsal telencephalon, the cerebral neocortex, and already at early stages prominent bulges begin t form into the ventricular lumen. One characteristic of ventral forebrain development is the early appearance of a non-apically dividing cell population away from the ventricle, which outnumbers from stages of midneurogenesis on apically dividing cells. Amongst these non-apically dividing cells a proportion divides in the ventricular zone, a region that in the neocortex is largely devoid of mitotic cells. These subapically dividing cells were termed according to their location subapical progenitors (SAP). The characterization of these SAPs both by immunohistochemistry and live imaging revealed a morphologically heterogeneous population, with cells bearing processes towards apical, basal or both directions in addition to cells without processes resembling the morphology of basal progenitors, during mitosis. Indeed, bipolar cells amongst these SAPs were characterized as a new type of radial glia, which does not reach the ventricular surface for mitosis but divides in the VZ and generates a basally migrating bRG. By this SAPs contribute to the seeding of the LGE SVZ with a cell type that is characteristic for enlarged SVZ, like the OSVZ in gyrified brains and fundamental for the formation of gyri and sulci. The longterm observation of RG lineages in the LGE uncovered the potential to generate large progeny at midneurogenesis. RG give rise to daughter cells which divide once more in the ventricular zone and generate cells with further proliferative potential, thereby amplifying the cellular output. This amplification of progenitor cells goes along with a shortening in cell cycle length, a feature observed also in the expanded germinal zones of gyrified cortices. In conclusion the developing murine LGE turns out to be a suitable model to study the cellular mechanisms of an expanded brain region

Long-term self-renewing stem cells in the adult mouse hippocampus identified by intravital imaging.

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.Wellcome Trus

Magyar Geofizika 1988

Introduction Bipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC). Methods We took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA's controlled for age, sex, body mass index, cardiovascular disease and smoking were performed. Results The levels of KYNA (F=5,579; p<.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F=5,394; p<.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F=11,357; p<.01). Discussion In conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states which should be capable to produce an even greater imbalance due to activation of key enzymes in the neurotoxic direction of KYN -conversion. These processes could finally be involved in the development of unspecific brain structural changes and cognitive deficits which are prevalent in BD. Further research should focus on state dependent changes in TRYCATs and its relation to cognition, brain structure and staging parameters

Time-Specific Effects of Spindle Positioning on Embryonic Progenitor Pool Composition and Adult Neural Stem Cell Seeding

International audienceThe developmental mechanisms regulating the number of adult neural stem cells (aNSCs) are largely unknown. Here we show that the cleavage plane orientation in murine embryonic radial glia cells (RGCs) regulates the number of aNSCs in the lateral ganglionic eminence (LGE). Randomizing spindle orientation in RGCs by overexpression of Insc or a dominant-negative form of Lgn (dnLgn) reduces the frequency of self-renewing asymmetric divisions while favoring symmetric divisions generating two SNPs. Importantly, these changes during embryonic development result in reduced seeding of aNSCs. Interestingly, no effects on aNSC numbers were observed when Insc was overexpressed in postnatal RGCs or aNSCs. These data suggest a new mechanism for controlling aNSC numbers and show that the role of spindle orientation during brain development is highly time and region dependent

Programming Hippocampal Neural Stem/Progenitor Cells into Oligodendrocytes Enhances Remyelination in the Adult Brain after Injury

Demyelinating diseases are characterized by a loss of oligodendrocytes leading to axonal degeneration and impaired brain function. Current strategies used for the treatment of demyelinating disease such as multiple sclerosis largely rely on modulation of the immune system. Only limited treatment options are available for treating the later stages of the disease, and these treatments require regenerative therapies to ameliorate the consequences of oligodendrocyte loss and axonal impairment. Directed differentiation of adult hippocampal neural stem/progenitor cells (NSPCs) into oligodendrocytes may represent an endogenous source of glial cells for cell-replacement strategies aiming to treat demyelinating disease. Here, we show that Ascl1-mediated conversion of hippocampal NSPCs into mature oligodendrocytes enhances remyelination in a diphtheria-toxin (DT)-inducible, genetic model for demyelination. These findings highlight the potential of targeting hippocampal NSPCs for the treatment of demyelinated lesions in the adult brain

Live imaging of neurogenesis in the adult mouse hippocampus

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

Chronic in vivo imaging defines age-dependent alterations of neurogenesis in the mouse hippocampus.

Acknowledgements: This work was supported by the European Research Council (STEMBAR to S.J.), the Swiss National Science Foundation (TMAG-3_209272, BSCGI0_157859, and 310030_196869 to S.J.), an UZH Candoc Fellowship (to Y.W.) and the Zurich Neuroscience Center. B.D.S acknowledges the support of the Royal Society (EP Abraham Professorship, RP/R1/180165). We thank D. C. Lie for comments on the manuscript.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