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Osseward, P. J., Amin, N. D., Moore, J. D., Temple, B. A., Barriga, B. K., Bachmann, L. C., Beltran, F., Gullo, M., Clark, R. C., Driscoll, S. P., Pfaff, S. L., Hayashi, M.
April 23, 2021
Neurons of the mouse spinal cord can be identified by any of several metrics, including what neurotransmitters they use, what cells they connect to, where they are located, and what neuroprogenitor gave rise to them. Osseward et al. generated a different metric, genetic signatures, and identified classes of local and projection neurons that were otherwise heterogeneous by other classification systems. With this focus on a cell's genetic signature, its neurotransmitter phenotype, which is accessible by a variety of transcriptional routes, can be seen as a parallel to convergent evolution in development. Science , this issue p.  Motor and sensory functions of the spinal cord are mediated by populations of cardinal neurons arising from separate progenitor lineages. However, each cardinal class is composed of multiple neuronal types with distinct molecular, anatomical, and physiological features, and there is not a unifying logic that systematically accounts for this diversity. We reasoned that the expansion of new neuronal types occurred in a stepwise manner analogous to animal speciation, and we explored this by defining transcriptomic relationships using a top-down approach. We uncovered orderly genetic tiers that sequentially divide groups of neurons by their motor-sensory, local-long range, and excitatory-inhibitory features. The genetic signatures defining neuronal projections were tied to neuronal birth date and conserved across cardinal classes. Thus, the intersection of cardinal class with projection markers provides a unifying taxonomic solution for systematically identifying distinct functional subsets. : /lookup/doi/10.1126/science.abe0690
Reid, D. A., Reed, P. J., Schlachetzki, J. C. M., Nitulescu, I. I., Chou, G., Tsui, E. C., Jones, J. R., Chandran, S., Lu, A. T., McClain, C. A., Ooi, J. H., Wang, T.-W., Lana, A. J., Linker, S. B., Ricciardulli, A. S., Lau, S., Schafer, S. T., Horvath, S., Dixon, J. R., Hah, N., Glass, C. K., Gage, F. H.
April 2, 2021
Humans have only a limited capacity to generate new neurons. These cells thus need to repair errors in the genome. To better understand this process, Reid et al. developed Repair-seq, a method to locate DNA repair within the genome of stem cell-derived neurons. DNA repair hotspots (DRHs) were more likely to occur within specific genomic features such as gene bodies as well as in genomic formations, open chromatin, and active regulatory regions. This method showed that repair was enriched at sites involved in neuronal function and identity. Furthermore, proteomic data indicated that genes in DRHs are enriched in Alzheimer's disease and that DRHs are more active in aging. These observations link neuronal DNA repair to aging and neurodegeneration. Science , this issue p.  Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system. : /lookup/doi/10.1126/science.abb9032
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