In the mammalian brain, neurogenesis continues only in few regions of the forebrain. The molecular signals governing neurogenesis in these unique neurogenic niches, however, are still ill defined. ...Here, we show that bone morphogenic protein (BMP)-mediated signaling is active in adult neural stem cells and is crucial to initiate the neurogenic lineage in the adult mouse subependymal zone. Conditional deletion of Smad4 in adult neural stem cells severely impairs neurogenesis, and this is phenocopied by infusion of Noggin, an extracellular antagonist of BMP. Smad4 deletion in stem, but not progenitor cells, as well as Noggin infusion lead to an increased number of Olig2-expressing progeny that migrate to the corpus callosum and differentiate into oligodendrocytes. Transplantation experiments further verified the cell-autonomous nature of this phenotype. Thus, BMP-mediated signaling via Smad4 is required to initiate neurogenesis from adult neural stem cells and suppress the alternative fate of oligodendrogliogenesis.
Ectopic expression of defined transcription factors can force direct cell-fate conversion from one lineage to another in the absence of cell division. Several transcription factor cocktails have ...enabled successful reprogramming of various somatic cell types into induced neurons (iNs) of distinct neurotransmitter phenotype. However, the nature of the intermediate states that drive the reprogramming trajectory toward distinct iN types is largely unknown. Here we show that successful direct reprogramming of adult human brain pericytes into functional iNs by Ascl1 and Sox2 encompasses transient activation of a neural stem cell-like gene expression program that precedes bifurcation into distinct neuronal lineages. During this transient state, key signaling components relevant for neural induction and neural stem cell maintenance are regulated by and functionally contribute to iN reprogramming and maturation. Thus, Ascl1- and Sox2-mediated reprogramming into a broad spectrum of iN types involves the unfolding of a developmental program via neural stem cell-like intermediates.
The 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.
•Randomization of the spindle orientation changes the progenitor pool composition•Overexpression of Insc or dnLgn reduces asymmetric self-renewing division of aRGCs•The change in embryonic progenitor pool leads to reduced seeding of adult NSCs•Insc influences the seeding of adult NSCs in a narrow developmental time window
Falk et al. uncover a new concept where the control of the division type in progenitor cells during embryonic development regulates the number of embryonic progenitor cells destined to become adult neural stem cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Glial control of neurogenesis Falk, Sven; Götz, Magdalena
Current opinion in neurobiology,
December 2017, 2017-Dec, 2017-12-00, 20171201, Volume:
47
Journal Article
Peer reviewed
Open access
•Glial cells are central components of all neurogenic niches.•Certain glial cells act as neural stem cells while others regulate neural stem cells.•A subset of embryonic radial glia cells give rise ...to adult neural stem cells.•Adult neural stem cell behavior is controlled by niche glial cells.•Non-stem cell glial cells can acquire stem cell features under certain conditions.
Glial cells are central components of all neurogenic niches in the embryonic as well as in the adult central nervous system. While neural stem cells (NSCs) themselves exhibit glial features the behavior of NSCs is also strongly influenced by niche glial cells. Recently, studies have begun to uncover a large variety of glial cell-extrinsic as well as intrinsic factors that play crucial roles in the control of NSCs and the regulation of the cellular output from the neurogenic niches. In this review, we focus on mechanisms underlying the formation of adult NSCs by embryonic radial glia cells, discuss the influence of niche glia cells on adult NSCs and examine how the neurogenic potential of glial cells is controlled.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Multiple signaling pathways regulate proliferation and differentiation of neural progenitor cells during early development of the central nervous system (CNS). In the spinal cord, dorsal signaling by ...bone morphogenic protein (BMP) acts primarily as a patterning signal, while canonical Wnt signaling promotes cell cycle progression in stem and progenitor cells. However, overexpression of Wnt factors or, as shown here, stabilization of the Wnt signaling component β-catenin has a more prominent effect in the ventral than in the dorsal spinal cord, revealing local differences in signal interpretation. Intriguingly, Wnt signaling is associated with BMP signal activation in the dorsal spinal cord. This points to a spatially restricted interaction between these pathways. Indeed, BMP counteracts proliferation promoted by Wnt in spinal cord neuroepithelial cells. Conversely, Wnt antagonizes BMP-dependent neuronal differentiation. Thus, a mutually inhibitory crosstalk between Wnt and BMP signaling controls the balance between proliferation and differentiation. A model emerges in which dorsal Wnt/BMP signal integration links growth and patterning, thereby maintaining undifferentiated and slow-cycling neural progenitors that form the dorsal confines of the developing spinal cord.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Direct lineage reprogramming challenges concepts of cellular identity.•During direct lineage reprogramming cellular identities change in the absence of mitosis.•Investigations on the temporal ...pattern of identity change elucidate basic aspects of cellular identity.
Direct lineage reprogramming challenges our traditional view on basic aspects of cellular identity, and in particular on processes crucial for identity acquisition. This is partly because in direct lineage reprogramming but not during natural differentiation processes changing cellular identity can occur in the absence of mitosis. Only recently, technologies emerged to deconstruct the cellular and molecular processes governing the transitory states a cell passes through on the journey from its original identity to the new target cell fate. Here we discuss arising concepts on the nature of these transitory states and the challenges and decisions cells must conquer to reach their new cellular identity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Neuronal heterogeneity has been established as a pillar of higher central nervous system function, but glial heterogeneity and its implications for neural circuit function are poorly understood. Here ...we show that the adult mouse dentate gyrus (DG) of the hippocampus is populated by molecularly distinct astrocyte subtypes that are associated with distinct DG layers. Astrocytes localized to different DG compartments also exhibit subtype-specific morphologies. Physiologically, astrocytes in upper DG layers form large syncytia, while those in lower DG compartments form smaller networks. Astrocyte subtypes differentially express glutamate transporters, which is associated with different amplitudes of glutamate transporter-mediated currents. Key molecular and morphological features of astrocyte diversity in the mice DG are conserved in humans. This adds another layer of complexity to our understanding of brain network composition and function, which will be crucial for further studies on astrocytes in health and disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The spatiotemporal control of proliferation and differentiation in neural stem cells (NSCs) is essential to produce a functional nervous system (NS). Stem cells in different areas and at different ...time points during development have to produce different types of cells in a precise manner. Recent studies uncovered a plethora of cell extrinsic as well as intrinsic factors that play crucial roles in the area-specific and stage-specific control of NSCs. Moreover, recapitulation of the spatiotemporal specification of NSCs in vitro opens new avenues for future applications. In this review, we have selected some key molecules to discuss the mechanisms underlying the spatiotemporal regulation of NSC development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Cortical projection neurons polarize and form an axon while migrating radially. Even though these dynamic processes are closely interwoven, they are regulated separately—the neurons terminate their ...migration when reaching their destination, the cortical plate, but continue to grow their axons. Here, we show that in rodents, the centrosome distinguishes these processes. Newly developed molecular tools modulating centrosomal microtubule nucleation combined with in vivo imaging uncovered that dysregulation of centrosomal microtubule nucleation abrogated radial migration without affecting axon formation. Tightly regulated centrosomal microtubule nucleation was required for periodic formation of the cytoplasmic dilation at the leading process, which is essential for radial migration. The microtubule nucleating factor γ-tubulin decreased at neuronal centrosomes during the migratory phase. As distinct microtubule networks drive neuronal polarization and radial migration, this provides insight into how neuronal migratory defects occur without largely affecting axonal tracts in human developmental cortical dysgeneses, caused by mutations in γ-tubulin.
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•Neurons polarize independently of centrosomal microtubule nucleation (CMN)•The centrosome loses γ-tubulin as neurons enter the cortical plate•CMN changes correlate with the cytoplasmic dilation in radially migrating neurons•CMN regulates radial migration independently of axon formation in the developing brain
Combining a novel expression system with live in vivo imaging, three-dimensional two-photon imaging, and centrosomal ablation, Vinopal and Dupraz et al. demonstrate that neurons need centrosomal microtubule nucleation for their radial migration but not axon formation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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