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Developmental Biology - Neurogenesis

Neural Stem Cells Continuously Generate

Brains may have the capacity for continuous improvement, adaptation, and incorporation of new cells over a lifetime...

Scientists once thought mammals were born with all the neurons they would ever need by adulthood. But, studies in the 1960s found neurons continue to generate in parts of the adult brain, and pioneering studies in the 1990s identified where and why. In the latest update, research shows how in mice, a single line of neural progenitor cells contribute to the hippocampus of the embryonic, postnatal, and adult mouse brain. These progenitor cells continuously generate neurons throughout the mouse lifetime.

The study appears March 28 in the journal Cell.
"Conceptually, this suggests our brains have the capacity for continuous improvement, adaptation, and incorporation of new cells into the circuitry. This turns out to be very important. The hippocampus is well known to be important for learning, memory, and mood regulation."

Hongjun Song PhD, Perelman School of Medicine, University of Pennsylvania, USA and senior author.

mouse hippocampus

Hopx+ precursor cells (GREEN OVALS) in mouse hippocampus (PURPLE) proliferate into Hopx+ neural progenitor cells, generating granule neurons (PURPLE CIRCLES).

Neurogenesis is believed to have two phases:

(1) Development occurs mostly in embryos to immediately after birth, when neurons generate from a stem cell into circuits for the full nervous system.
(2) Adult neurogenesis originating from a special population of neural stem cells are "set aside" and distinct from precursor generating neurons during embryogenesis.

But, this new research believes it is a continuous process:

(1) Labelling precursor mouse neural stem cells in early brain development, allows each cell line to be followed through development into adulthood.
(2) With precursor cells labeled, neural stem cells are seen to continuously generate neurons throughout an animals' lifetime.

RNA-seq and ATAC-seq analyses confirming all cells in labeled lineages have a common molecular signature and the same developmental dynamics.
"Earlier studies have suggested that specific parts of the brain, such as the olfactory bulb and the hippocampus, can generate neurons. Until this study, it wasn't clear how this happens. We've shown for the first time, in a mammalian brain development is ongoing from the beginning, and that this one process continues over a lifetime."

Hongjun Song PhD

While adult neurogenesis in humans and other primates is actively being discussed in the field, more research is still needed to determine just how stem cell generation seen in mice pertains to other mammals. The investigators plan to continue studying it in more detail as they want to find ways to increase or preserve neurogenesis while determining its regulation at the molecular level.
"This paper has implications for understanding how the brain maintains a 'young' state for learning and memory. If we could harness this capacity and this mechanism, we may be able to repair and regenerate parts of the brain."

Guo-li Ming PhD, Department of Neuroscience and Mahoney Institute for Neurosciences; Department of Cell and Developmental Biology; Institute for Regenerative Medicine; and Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA, and co-senior author.

High-throughput mapping of cellular differentiation hierarchies from single-cell data promises to empower systematic interrogations of vertebrate development and disease. Here we applied single-cell RNA sequencing to >92,000 cells from zebrafish embryos during the first day of development. Using a graph-based approach, we mapped a cell-state landscape that describes axis patterning, germ layer formation, and organogenesis. We tested how clonally related cells traverse this landscape by developing a transposon-based barcoding approach (TracerSeq) for reconstructing single-cell lineage histories. Clonally related cells were often restricted by the state landscape, including a case in which two independent lineages converge on similar fates. Cell fates remained restricted to this landscape in embryos lacking the chordin gene. We provide web-based resources for further analysis of the single-cell data.

Daniel A. Berg, Yijing Su, Dennisse Jimenez-Cyrus, Aneek Patel, Nancy Huang, David Morizet, Stephanie Lee, Reeti Shah, Francisca Rojas Ringeling, Rajan Jain, Jonathan A. Epstein, Qing-Feng Wu, Stefan Canzar, Guo-Li Ming, Hongjun Song and Allison M. Bond.

The authors thank K.M. Christian for comments, members of Ming and Song laboratories for discussion, D. Johnson and B. Temsamrit for technical support, J. Schnoll for lab coordination, and V. Yoon and Y. Huang for providing Apoe-GFP transgenic mouse tissue. This work was supported by grants from the NIH (P01NS097206 and R37NS047344 to H.S., R35NS097370 and R01MH105128 to G.-L.M., R35HL140018 to J.A.E., and DP2HL147123 to R.J.) and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to G.-L.M.). R.J. was supported by the Burroughs Wellcome Foundation. D.A.B. was supported by an EMBO postdoctoral fellowship and a grant from the Swedish Research Council.

The authors declare no competing interests.

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Apr 3 2019   Fetal Timeline   Maternal Timeline   News  

Image of a mouse hippocampus with adult neural stem cells (GREEN). CREDIT: Berg et al/Cell

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