Molecular cascade reveals sequential milestones underlying hippocampal neural stem cell development into an adult state
Dennisse Jimenez-Cyrus,
Vijay S. Adusumilli,
Max H. Stempel,
Sandra Maday,
Guo-li Ming,
Hongjun Song,
Allison M. Bond
Affiliations
Dennisse Jimenez-Cyrus
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Vijay S. Adusumilli
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Max H. Stempel
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Sandra Maday
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Guo-li Ming
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Hongjun Song
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding author
Allison M. Bond
Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding author
Summary: Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones, and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here, we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular reactive oxygen species level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain.
