Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing

The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells. We observed shifts in the molecular identity of quiescent and proliferating radial glia and granule cells during the postnatal period that were then maintained through adult stages. In contrast, intermediate progenitor cells, neuroblasts, and immature granule cells were nearly indistinguishable at all ages. These findings demonstrate the fundamental similarity of postnatal and adult neurogenesis in the hippocampus and pinpoint the early postnatal transformation of radial glia from embryonic progenitors to adult quiescent stem cells.Using single-cell RNA-seq, the authors show that early developmental neurogenesis in the dentate gyrus of the hippocampus is largely conserved in the adult, but with a perinatal transformation of stem cells to an adult type.

[1]  J. Altman,et al.  Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats , 1965, The Journal of comparative neurology.

[2]  J. Hinds,et al.  Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. , 1977, Science.

[3]  J. Altman,et al.  Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods , 1990, The Journal of comparative neurology.

[4]  A. Fine,et al.  Live astrocytes visualized by green fluorescent protein in transgenic mice. , 1997, Developmental biology.

[5]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[6]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[7]  Gerd Kempermann,et al.  Experience-Induced Neurogenesis in the Senescent Dentate Gyrus , 1998, The Journal of Neuroscience.

[8]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[9]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[10]  E Gould,et al.  Hippocampal neurogenesis in adult Old World primates. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. Götz,et al.  Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. , 2000, Development.

[12]  F. Gage,et al.  Mammalian neural stem cells. , 2000, Science.

[13]  J. García-Verdugo,et al.  Astrocytes Give Rise to New Neurons in the Adult Mammalian Hippocampus , 2001, The Journal of Neuroscience.

[14]  M. Sofroniew,et al.  GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain , 2004, Nature Neuroscience.

[15]  Gerd Kempermann,et al.  Milestones of neuronal development in the adult hippocampus , 2004, Trends in Neurosciences.

[16]  G. Kempermann,et al.  Differential regulation of gliogenesis in the context of adult hippocampal neurogenesis in mice , 2004, Glia.

[17]  G. Westbrook,et al.  Delayed Development of Adult-Generated Granule Cells in Dentate Gyrus , 2006, The Journal of Neuroscience.

[18]  G. Westbrook,et al.  Functional maturation of adult‐generated granule cells , 2006, Hippocampus.

[19]  A. F. Schinder,et al.  The Timing of Neuronal Development in Adult Hippocampal Neurogenesis , 2006, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[20]  D. Amaral,et al.  The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies). , 2007, Progress in brain research.

[21]  Geoffrey E. Hinton,et al.  Visualizing Data using t-SNE , 2008 .

[22]  A. Kriegstein,et al.  Distinct behaviors of neural stem and progenitor cells underlie cortical neurogenesis , 2008, The Journal of comparative neurology.

[23]  Arnold Kriegstein,et al.  The glial nature of embryonic and adult neural stem cells. , 2009, Annual review of neuroscience.

[24]  V. Tarabykin,et al.  AP2γ regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex , 2009, Nature Neuroscience.

[25]  Erika Pastrana,et al.  Simultaneous prospective purification of adult subventricular zone neural stem cells and their progeny , 2009, Proceedings of the National Academy of Sciences.

[26]  Gerald J. Sun,et al.  In Vivo Clonal Analysis Reveals Self-Renewing and Multipotent Adult Neural Stem Cell Characteristics , 2011, Cell.

[27]  S. Kernie,et al.  Developmental profiling of postnatal dentate gyrus progenitors provides evidence for dynamic cell‐autonomous regulation , 2011, Hippocampus.

[28]  Jenny Hsieh Orchestrating transcriptional control of adult neurogenesis. , 2012, Genes & development.

[29]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[30]  H. Schorle,et al.  The role of transcription factor Tcfap2c/TFAP2C in trophectoderm development. , 2012, Reproductive biomedicine online.

[31]  M. Araúzo-Bravo,et al.  Transcription Factor TFAP2C Regulates Major Programs Required for Murine Fetal Germ Cell Maintenance and Haploinsufficiency Predisposes to Teratomas in Male Mice , 2013, PloS one.

[32]  A. Álvarez-Buylla,et al.  Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice , 2013, Proceedings of the National Academy of Sciences.

[33]  M. Araúzo-Bravo,et al.  Metabolic control of adult neural stem cell activity by Fasn-dependent lipogenesis , 2012, Nature.

[34]  M. Götz,et al.  Radial glia – from boring cables to stem cell stars , 2013, Development.

[35]  Allan R. Jones,et al.  Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates , 2013, Development.

[36]  M. Knobloch,et al.  SPOT14-Positive Neural Stem/Progenitor Cells in the Hippocampus Respond Dynamically to Neurogenic Regulators , 2014, Stem cell reports.

[37]  R. Baldock,et al.  Kaufman’s Atlas of Mouse Development Supplement , 2015 .

[38]  S. Linnarsson,et al.  Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq , 2015, Science.

[39]  K. Fabel,et al.  Development of the adult neurogenic niche in the hippocampus of mice , 2015, Front. Neuroanat..

[40]  S. Ge,et al.  Viral and transgenic reporters and genetic analysis of adult neurogenesis. , 2015, Cold Spring Harbor perspectives in biology.

[41]  David W. Nauen,et al.  Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis. , 2015, Cell stem cell.

[42]  K. Fabel,et al.  Lysophosphatidic Acid Receptor Is a Functional Marker of Adult Hippocampal Precursor Cells , 2016, Stem cell reports.

[43]  Wanyeon Kim,et al.  TFAP2C-mediated upregulation of TGFBR1 promotes lung tumorigenesis and epithelial–mesenchymal transition , 2016, Experimental & Molecular Medicine.

[44]  A. Regev,et al.  Div-Seq: A single nucleus RNA-Seq method reveals dynamics of rare adult newborn neurons in the CNS , 2016, bioRxiv.

[45]  J. Gonçalves,et al.  Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior , 2016, Cell.

[46]  M. Götz,et al.  Neurogenesis in the Developing and Adult Brain-Similarities and Key Differences. , 2016, Cold Spring Harbor perspectives in biology.

[47]  Jens Hjerling-Leffler,et al.  Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system , 2016, Science.

[48]  Wanyeon Kim,et al.  TFAP2C promotes lung tumorigenesis and aggressiveness through miR-183- and miR-33a-mediated cell cycle regulation , 2017, Oncogene.

[49]  N. Sousa,et al.  AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior , 2017, Molecular Psychiatry.