Adult mammals have lost multi-tissue regenerative capacity, except for the distal digit, which is able to regenerate via mechanisms that remain largely unknown. Here, we show that, after adult mouse ...distal digit removal, nerve-associated Schwann cell precursors (SCPs) dedifferentiate and secrete growth factors that promote expansion of the blastema and digit regeneration. When SCPs were dysregulated or ablated, mesenchymal precursor proliferation in the blastema was decreased and nail and bone regeneration were impaired. Transplantation of exogenous SCPs rescued these regeneration defects. We found that SCPs secrete factors that promote self-renewal of mesenchymal precursors, and we used transcriptomic and proteomic analysis to define candidate factors. Two of these, oncostatin M (OSM) and platelet-derived growth factor AA (PDGF-AA), are made by SCPs in the regenerating digit and rescued the deficits in regeneration caused by loss of SCPs. As all peripheral tissues contain nerves, these results could have broad implications for mammalian tissue repair and regeneration.
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•Schwann cell precursors (SCPs) enter the regenerating digit tip•Ablation of SCPs by inducible deletion or denervation inhibits regeneration•SCPs secrete growth factors to promote mesenchymal cell proliferation•Oncostatin M and PDGF-AA can rescue regeneration in a denervated digit tip
Johnston et al. show that, during regeneration of the mouse digit tip, nerve-associated Schwann cell precursors dedifferentiate and move into the injured tissue, where they secrete paracrine factors, including oncostatin M and PDGF-AA, to promote mesenchymal cell proliferation, expansion of the blastema, and regeneration.
Although endogenous recruitment of adult neural stem cells has been proposed as a therapeutic strategy, clinical approaches for achieving this are lacking. Here, we show that metformin, a widely used ...drug, promotes neurogenesis and enhances spatial memory formation. Specifically, we show that an atypical PKC-CBP pathway is essential for the normal genesis of neurons from neural precursors and that metformin activates this pathway to promote rodent and human neurogenesis in culture. Metformin also enhances neurogenesis in the adult mouse brain in a CBP-dependent fashion, and in so doing enhances spatial reversal learning in the water maze. Thus, metformin, by activating an aPKC-CBP pathway, recruits neural stem cells and enhances neural function, thereby providing a candidate pharmacological approach for nervous system therapy.
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► aPKCs ζ and ι play distinct roles in the neural precursor to neuron transition ► Metformin enhances mammalian neurogenesis via the aPKC-CBP pathway ► Metformin increases adult neurogenesis in vivo and enhances spatial memory
Metformin, a drug used to treat type 2 diabetes, increases adult neurogenesis in vivo. Metformin activates aPKC-CBP signaling to recruit neural stem cells and improve spatial learning.
Here, we have addressed the mechanisms that determine genesis of the correct numbers of neurons during development, focusing on the embryonic cortex. We identify in neural precursors a repressive ...complex involving eIF4E1 and its binding partner 4E-T that coordinately represses translation of proteins that determine neurogenesis. This eIF4E1/4E-T complex is present in granules with the processing body proteins Lsm1 and Rck, and disruption of this complex causes premature and enhanced neurogenesis and neural precursor depletion. Analysis of the 4E-T complex shows that it is highly enriched in mRNAs encoding transcription factors and differentiation-related proteins. These include the proneurogenic bHLH mRNAs, which colocalize with 4E-T in granules and whose protein products are aberrantly upregulated following knockdown of eIF4E, 4E-T, or processing body proteins. Thus, neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic proteins to determine appropriate neurogenesis.
•An eIF4E/4E-T complex represses neurogenesis and maintains radial precursors•Disruption of the eIF4E/4E-T complex or P-body proteins enhances neurogenesis•This complex binds mRNAs encoding transcription and cell differentiation regulators•Disruption of the eIF4E/4E-T complex derepresses translation of proneurogenic bHLHs
Yang et al. show that translational control in neural precursors is crucial for determining appropriate neurogenesis. Neural precursors are transcriptionally primed to generate neurons, but an eIF4E/4E-T complex sequesters and represses translation of proneurogenic mRNAs to prevent premature differentiation.
Peripheral innervation plays an important role in regulating tissue repair and regeneration. Here we provide evidence that injured peripheral nerves provide a reservoir of mesenchymal precursor cells ...that can directly contribute to murine digit tip regeneration and skin repair. In particular, using single-cell RNA sequencing and lineage tracing, we identify transcriptionally distinct mesenchymal cell populations within the control and injured adult nerve, including neural crest-derived cells in the endoneurium with characteristics of mesenchymal precursor cells. Culture and transplantation studies show that these nerve-derived mesenchymal cells have the potential to differentiate into non-nerve lineages. Moreover, following digit tip amputation, neural crest-derived nerve mesenchymal cells contribute to the regenerative blastema and, ultimately, to the regenerated bone. Similarly, neural crest-derived nerve mesenchymal cells contribute to the dermis during skin wound healing. These findings support a model where peripheral nerves directly contribute mesenchymal precursor cells to promote repair and regeneration of injured mammalian tissues.
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•Peripheral nerves contain four transcriptionally distinct mesenchymal populations•Endoneurial Pdgfra-positive cells have mesenchymal precursor properties•Nerve mesenchymal cells contribute to bone formation during digit tip regeneration•Transplanted and endogenous nerve mesenchymal cells contribute to dermal repair
Carr et al. demonstrate that peripheral nerves contain mesenchymal precursor-like cells that participate in repair of damaged mesenchymal tissues. Utilizing scRNA-seq, lineage tracing, and transplantation approaches, the authors show that neural crest-derived endoneurial mesenchymal precursor cells generate bone and dermal cells during digit tip regeneration and skin wound healing.
The mammalian neocortex underlies our perception of sensory information, performance of motor activities, and higher-order cognition. During mammalian embryogenesis, radial glial precursor cells ...sequentially give rise to diverse populations of excitatory cortical neurons, followed by astrocytes and oligodendrocytes. A subpopulation of these embryonic neural precursors persists into adulthood as neural stem cells, which give rise to inhibitory interneurons and glia. Although the intrinsic mechanisms instructing the genesis of these distinct progeny have been well-studied, most work to date has focused on transcriptional, epigenetic, and cell-cycle control. Recent studies, however, have shown that posttranscriptional mechanisms also regulate the cell fate choices of transcriptionally primed neural precursors during cortical development. These mechanisms are mediated primarily by RNA-binding proteins and microRNAs that coordinately regulate mRNA translation, stability, splicing, and localization. Together, these findings point to an extensive network of posttranscriptional control and provide insight into both normal cortical development and disease. They also add another layer of complexity to brain development and raise important biological questions for future investigation.
Neurogenesis requires the concerted action of numerous genes that are regulated at multiple levels. However, how different layers of gene regulation are coordinated to promote neurogenesis is not ...well understood. We show that the neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) negatively regulates REST (NRSF), a transcriptional repressor of genes required for neurogenesis. nSR100 directly promotes alternative splicing of REST transcripts to produce a REST isoform (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells. Conversely, REST directly represses nSR100 in nonneural cells to prevent the activation of neural-specific splicing events. Consistent with a critical role for nSR100 in the inhibition of REST activity, blocking nSR100 expression in the developing mouse brain impairs neurogenesis. Our results thus reveal a fundamental role for direct regulatory interactions between a splicing activator and transcription repressor in the control of the multilayered regulatory programs required for neurogenesis.
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► nSR100 negatively regulates the REST transcriptional repressor during neurogenesis ► nSR100 represses REST via activation of a neural-specific splicing switch ► REST directly represses nSR100 expression in nonneural cells ► Loss of nSR100 promotes REST-mediated repression of neurogenesis
Adult neural stem cells (NSCs) derive from embryonic precursors, but little is known about how or when this occurs. We have addressed this issue using single-cell RNA sequencing at multiple ...developmental time points to analyze the embryonic murine cortex, one source of adult forebrain NSCs. We computationally identify all major cortical cell types, including the embryonic radial precursors (RPs) that generate adult NSCs. We define the initial emergence of RPs from neuroepithelial stem cells at E11.5. We show that, by E13.5, RPs express a transcriptional identity that is maintained and reinforced throughout their transition to a non-proliferative state between E15.5 and E17.5. These slowly proliferating late embryonic RPs share a core transcriptional phenotype with quiescent adult forebrain NSCs. Together, these findings support a model wherein cortical RPs maintain a core transcriptional identity from embryogenesis through to adulthood and wherein the transition to a quiescent adult NSC occurs during late neurogenesis.
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•Single-cell RNA-seq identifies transcriptional profiles of cortical precursors•Radial precursors (RPs) express a core identity reinforced throughout development•RPs adopt a non-proliferative state during late neurogenesis•RPs share a transcriptional core identity with adult B1 neural stem cells
Yuzwa et al. use single-cell RNA-seq to define the transcriptional identity of precursor cells in the embryonic mouse cortex and, in so doing, characterize the developmental emergence of adult forebrain neural stem cells.
Here, we investigate the origin and nature of blastema cells that regenerate the adult murine digit tip. We show that Pdgfra-expressing mesenchymal cells in uninjured digits establish the ...regenerative blastema and are essential for regeneration. Single-cell profiling shows that the mesenchymal blastema cells are distinct from both uninjured digit and embryonic limb or digit Pdgfra-positive cells. This unique blastema state is environmentally determined; dermal fibroblasts transplanted into the regenerative, but not non-regenerative, digit express blastema-state genes and contribute to bone regeneration. Moreover, lineage tracing with single-cell profiling indicates that endogenous osteoblasts or osteocytes acquire a blastema mesenchymal transcriptional state and contribute to both dermis and bone regeneration. Thus, mammalian digit tip regeneration occurs via a distinct adult mechanism where the regenerative environment promotes acquisition of a blastema state that enables cells from tissues such as bone to contribute to the regeneration of other mesenchymal tissues such as the dermis.
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•Pdgfra-expressing mesenchymal cells from uninjured digits establish the blastema•Adult digit tip regeneration is distinct from embryonic digit development•The blastema state is environmentally determined•The regenerative environment enables mesenchymal lineage plasticity
Storer et al. use lineage tracing, single-cell RNA sequencing, and cell transplantation to define the transcriptional identity of the mesenchymal cells comprising the blastema and the major transitions during mammalian digit tip regeneration. The regenerative environment determines the adult blastema state and confers mesenchymal lineage flexibility.
Despite the remarkable regenerative capacity of mammalian skin, an adult dermal stem cell has not yet been identified. Here, we investigated whether skin-derived precursors (SKPs) might fulfill such ...a role. We show that SKPs derive from Sox2
+ hair follicle dermal cells and that these two cell populations are similar with regard to their transcriptome and functional properties. Both clonal SKPs and endogenous Sox2
+ cells induce hair morphogenesis, differentiate into dermal cell types, and home to a hair follicle niche upon transplantation. Moreover, hair follicle-derived SKPs self-renew, maintain their multipotency, and serially reconstitute hair follicles. Finally, grafting experiments show that follicle-associated dermal cells move out of their niche to contribute cells for dermal maintenance and wound-healing. Thus, SKPs derive from Sox2
+ follicle-associated dermal precursors and display functional properties predicted of a dermal stem cell, contributing to dermal maintenance, wound-healing, and hair follicle morphogenesis.
During development of the mammalian nervous system, neural stem cells generate neurons first and glia second, thereby allowing the initial establishment of neural circuitry, and subsequent matching ...of glial numbers and position to that circuitry. Here, we have reviewed work addressing the mechanisms underlying this timed cell genesis, with a particular focus on the developing cortex. These studies have defined an intriguing interplay between intrinsic epigenetic status, transcription factors, and environmental cues, all of which work together to establish this fascinating and complex biological timing mechanism.
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