Signaling through BMPR-IA regulates quiescence and long-term activity of neural stem cells in the adult hippocampus.

SummaryNeural stem cells (NSCs) in the adult hippocampus divide infrequently, and the molecules that modulate their quiescence are largely unknown. Here, we show that bone morphogenetic protein (BMP) signaling is active in hippocampal NSCs, downstream of BMPR-IA. BMPs reversibly diminish proliferation of cultured NSCs while maintaining their undifferentiated state. In vivo, acute blockade of BMP signaling in the hippocampus by intracerebral infusion of Noggin first recruits quiescent NSCs into the cycle and increases neurogenesis; subsequently, it leads to decreased stem cell division and depletion of precursors and newborn neurons. Consistently, selective ablation of Bmpr1a in hippocampal …

Editorial overview: Fluidity of cell fates – from reprogramming to repair

A critical period for experience-dependent remodeling of adult-born neuron connectivity.

Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is a process regulated by experience. To understand whether experience also modifies the connectivity of new neurons, we systematically investigated changes in their innervation following environmental enrichment (EE). We found that EE exposure between 2-6 weeks following neuron birth, rather than merely increasing the number of new neurons, profoundly affected their pattern of monosynaptic inputs. Both local innervation by interneurons and to even greater degree long-distance innervation by cortical neurons were markedly enhanced. Furthermore, following EE, new neurons received inputs from CA3 and CA1 inhibitory neurons that w…

Reprogramming of Pericyte-Derived Cells of the Adult Human Brain into Induced Neuronal Cells

SummaryReprogramming of somatic cells into neurons provides a new approach toward cell-based therapy of neurodegenerative diseases. A major challenge for the translation of neuronal reprogramming into therapy is whether the adult human brain contains cell populations amenable to direct somatic cell conversion. Here we show that cells from the adult human cerebral cortex expressing pericyte hallmarks can be reprogrammed into neuronal cells by retrovirus-mediated coexpression of the transcription factors Sox2 and Mash1. These induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrat…

Transcriptional Mechanisms of Proneural Factors and REST in Regulating Neuronal Reprogramming of Astrocytes

Summary Direct lineage reprogramming induces dramatic shifts in cellular identity, employing poorly understood mechanisms. Recently, we demonstrated that expression of Neurog2 or Ascl1 in postnatal mouse astrocytes generates glutamatergic or GABAergic neurons. Here, we take advantage of this model to study dynamics of neuronal cell fate acquisition at the transcriptional level. We found that Neurog2 and Ascl1 rapidly elicited distinct neurogenic programs with only a small subset of shared target genes. Within this subset, only NeuroD4 could by itself induce neuronal reprogramming in both mouse and human astrocytes, while co-expression with Insm1 was required for glutamatergic maturation. Cu…

Sox2-Mediated Conversion of NG2 Glia into Induced Neurons in the Injured Adult Cerebral Cortex

Summary The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 glia into induced doublecortin (DCX)+ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX+ cells. Neurons induced following …

Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb

Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple typ…

Selective Adhesion of Cells from Different Telencephalic Regions

AbstractWe asked whether specification of different regions of the rodent and avian telencephalon during development involved the acquisition of differential adhesive properties. Cells from different regions were aggregated in a short-term aggregation assay, and their segregation was analyzed. Both neurons and precursor cells from cortex segregate from striatal cells at early, but not later, stages, whereas cells from rodent neocortex and hippocampus segregated only during later stages. Segregation was abolished when Ca2+-dependent but not Ca2+-independent adhesion molecules were selectively removed. Thus, selective adhesion appears to be a conserved mechanism that restricts cellular mixing…

Inflammation-Induced Alteration of Astrocyte Mitochondrial Dynamics Requires Autophagy for Mitochondrial Network Maintenance

Accumulating evidence suggests that changes in the metabolic signature of astrocytes underlie their response to neuroinflammation, but how proinflammatory stimuli induce these changes is poorly understood. By monitoring astrocytes following acute cortical injury, we identified a differential and region-specific remodeling of their mitochondrial network: while astrocytes within the penumbra of the lesion undergo mitochondrial elongation, those located in the core-the area invaded by proinflammatory cells-experience transient mitochondrial fragmentation. In brain slices, proinflammatory stimuli reproduced localized changes in mitochondrial dynamics, favoring fission over fusion. This effect w…

Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-w…

Direct pericyte-to-neuron reprogramming via unfolding of a neural stem cell-like program

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…