Dbx2, an Aging-Related Homeobox Gene, Inhibits the Proliferation of Adult Neural Progenitors

The subventricular zone (SVZ) of the adult mouse brain contains quiescent neural stem cells, which can be activated (aNSCs) to generate transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. Neurogenesis declines during aging, as the aged SVZ niche causes transcriptomic changes that promote NSC quiescence and decrease proliferating neural/stem progenitor cells (NSPCs). The transcription factors mediating these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in aged SVZ NSPCs and inhibits NSPC culture growth. Here, we report that Dbx2 is repressed by Epidermal Growth Factor Receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. We show that Dbx2 inhibits NSPC proliferation by hindering the G2/M transition and elucidate the transcriptomic networks modulated by Dbx2, highlighting its role in the downregulation of the cell cycle molecular pathways. Accordingly, Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a molecular node relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.

[1]  I. Weissman,et al.  Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain , 2022, Nature Aging.

[2]  A. Rábano,et al.  Impact of neurodegenerative diseases on human adult hippocampal neurogenesis , 2021, Science.

[3]  M. Clements,et al.  LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells , 2021, Nature Communications.

[4]  F. Pratesi,et al.  Manipulation of EGFR-Induced Signaling for the Recruitment of Quiescent Neural Stem Cells in the Adult Mouse Forebrain , 2021, Frontiers in Neuroscience.

[5]  F. Guillemot,et al.  Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population , 2021, Cell stem cell.

[6]  I. Fariñas,et al.  Adult Neural Stem Cells Are Alerted by Systemic Inflammation through TNF-α Receptor Signaling. , 2020, Cell stem cell.

[7]  J. Glover,et al.  A versatile toolbox for semi-automatic cell-by-cell object-based colocalization analysis , 2020, Scientific Reports.

[8]  Ashley M. Laughney,et al.  High-resolution mouse subventricular zone stem-cell niche transcriptome reveals features of lineage, anatomy, and aging , 2020, Proceedings of the National Academy of Sciences.

[9]  A. Brunet,et al.  Aging and Rejuvenation of Neural Stem Cells and Their Niches. , 2020, Cell stem cell.

[10]  E. Cundari,et al.  X-ray irradiated cultures of mouse cortical neural stem/progenitor cells recover cell viability and proliferation with dose-dependent kinetics , 2020, Scientific Reports.

[11]  F. Guillemot,et al.  Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest , 2019, Neuron.

[12]  A. Ballabio,et al.  Enhanced lysosomal degradation maintains the quiescent state of neural stem cells , 2019, Nature Communications.

[13]  Mark M. Davis,et al.  Single cell analysis reveals T cell infiltration in old neurogenic niches , 2019, Nature.

[14]  David J. Jörg,et al.  Early Stem Cell Aging in the Mature Brain , 2019, bioRxiv.

[15]  S. Gaetani,et al.  Molecular Signatures of the Aging Brain: Finding the Links Between Genes and Phenotypes , 2019, Neurotherapeutics.

[16]  Jesús Ávila,et al.  Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease , 2019, Nature Medicine.

[17]  A. Marciniak-Czochra,et al.  Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain , 2019, Cell.

[18]  A. Álvarez-Buylla,et al.  Neural stem cells: origin, heterogeneity and regulation in the adult mammalian brain , 2019, Development.

[19]  E. Cacci,et al.  Molecular Mechanisms of Neurogenic Aging in the Adult Mouse Subventricular Zone , 2019, Journal of experimental neuroscience.

[20]  Fabian J Theis,et al.  Increasing Neural Stem Cell Division Asymmetry and Quiescence Are Predicted to Contribute to the Age-Related Decline in Neurogenesis. , 2018, Cell reports.

[21]  Aristotelis Misios,et al.  Single-Cell Transcriptomics Characterizes Cell Types in the Subventricular Zone and Uncovers Molecular Defects Impairing Adult Neurogenesis. , 2018, Cell reports.

[22]  A. Brand,et al.  Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence , 2018, Science.

[23]  E. Passegué,et al.  Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging , 2018, Science.

[24]  P. Bovolenta,et al.  Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline , 2018, Aging cell.

[25]  Mauro J. Muraro,et al.  Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy , 2018, Proceedings of the National Academy of Sciences.

[26]  Sally Temple,et al.  Non-monotonic Changes in Progenitor Cell Behavior and Gene Expression during Aging of the Adult V-SVZ Neural Stem Cell Niche , 2017, Stem cell reports.

[27]  Taihei Yamada,et al.  Heparan sulfate alterations in extracellular matrix structures and fibroblast growth factor‐2 signaling impairment in the aged neurogenic niche , 2017, Journal of neurochemistry.

[28]  Juehua Yu,et al.  Single-cell transcriptomics reveals gene signatures and alterations associated with aging in distinct neural stem/progenitor cell subpopulations , 2017, Protein & Cell.

[29]  E. Cacci,et al.  Transcriptional response of Hoxb genes to retinoid signalling is regionally restricted along the neural tube rostrocaudal axis , 2017, Royal Society Open Science.

[30]  A. Álvarez-Buylla,et al.  The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis. , 2016, Cold Spring Harbor perspectives in biology.

[31]  Fabian J Theis,et al.  Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone , 2015, Nature Neuroscience.

[32]  Raphael Gottardo,et al.  Orchestrating high-throughput genomic analysis with Bioconductor , 2015, Nature Methods.

[33]  Erika Pastrana,et al.  Prospective Identification and Purification of Quiescent Adult Neural Stem Cells from Their In Vivo Niche , 2014, Neuron.

[34]  A. Cebrian-Silla,et al.  Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain , 2013, EMBO molecular medicine.

[35]  Thomas R. Gingeras,et al.  STAR: ultrafast universal RNA-seq aligner , 2013, Bioinform..

[36]  C. Perrone-Capano,et al.  Restriction of Neural Precursor Ability to Respond to Nurr1 by Early Regional Specification , 2012, PloS one.

[37]  Kevin W Eliceiri,et al.  NIH Image to ImageJ: 25 years of image analysis , 2012, Nature Methods.

[38]  G. Fishell,et al.  Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. , 2011, Cell stem cell.

[39]  Mark D. Robinson,et al.  edgeR: a Bioconductor package for differential expression analysis of digital gene expression data , 2009, Bioinform..

[40]  G. Kempermann,et al.  Neurogenesis in the adult hippocampus , 2007, Cell and Tissue Research.

[41]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Christopher Gregg,et al.  Aging Results in Reduced Epidermal Growth Factor Receptor Signaling, Diminished Olfactory Neurogenesis, and Deficits in Fine Olfactory Discrimination , 2004, The Journal of Neuroscience.

[43]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[44]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[45]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[46]  C. Allis,et al.  Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation , 1997, Chromosoma.