title: Heterogeneously expressed fezf2 patterns gradient Notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells.
abstract: Balancing quiescence, self-renewal, and differentiation in adult stem cells is critical for tissue homeostasis. The underlying mechanisms, however, remain incompletely understood. Here we identify Fezf2 as a novel regulator of fate balance in adult zebrafish dorsal telencephalic neural stem cells (NSCs). Transgenic reporters show intermingled fezf2-GFP(hi) quiescent and fezf2-GFP(lo) proliferative NSCs. Constitutive or conditional impairment of fezf2 activity demonstrates its requirement for maintaining quiescence. Analyses of genetic chimeras reveal a dose-dependent role of fezf2 in NSC activation, suggesting that the difference in fezf2 levels directionally biases fate. Single NSC profiling coupled with genetic analysis further uncovers a fezf2-dependent gradient Notch activity that is high in quiescent and low in proliferative NSCs. Finally, fezf2-GFP(hi) quiescent and fezf2-GFP(lo) proliferative NSCs are observed in postnatal mouse hippocampus, suggesting possible evolutionary conservation. Our results support a model in which fezf2 heterogeneity patterns gradient Notch activity among neighbors that is critical to balance NSC fate.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Graduate Program in Neuroscience, Institute of Human Genetics, Department of Molecular Genetics, Ohio State University, Columbus, Ohio 43210.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Berberoglu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Institute of Human Genetics.
authors.forename: Zhiqiang
authors.identifier: http://orcid.org/0000-0001-6259-915X
authors.initials: Z
authors.lastname: Dong
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurology.
authors.forename: Guangnan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Biophysics.
authors.forename: Jiashun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Institute of Human Genetics, Graduate Program in Cell and Molecular Biology, Department of Biology, San Francisco State University, San Francisco, California 94132.
authors.forename: Luz del Carmen G
authors.initials: Ldel C
authors.lastname: Trejo Martinez
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Institute of Human Genetics.
authors.forename: Jisong
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Institute of Human Genetics.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Wagle
authors.affiliation: Department of Neurological Surgery, and.
authors.forename: Brian
authors.initials: B
authors.lastname: Reichholf
authors.affiliation: Department of Neurological Surgery, and Brain Tumor Research Center, University of California, San Francisco, California 94143-2811.
authors.forename: Claudia
authors.initials: C
authors.lastname: Petritsch
authors.affiliation: Department of Biochemistry and Biophysics.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Graduate Program in Neuroscience, Department of Neurology.
authors.forename: Samuel J
authors.identifier: http://orcid.org/0000-0001-8599-1613
authors.initials: SJ
authors.lastname: Pleasure
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Graduate Program in Neuroscience, Institute of Human Genetics, State Key Laboratory of Genetic Engineering and the Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, China, and su.guo@ucsf.edu.
authors.forename: Su
authors.identifier: http://orcid.org/0000-0002-7342-0108
authors.initials: S
authors.lastname: Guo
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology; D051880:Receptors, Notch / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D051880:Receptors, Notch; C412364:Zfp312 protein, mouse
keywords: adult neurogenesis; hippocampus; radial glia; self-renewal; single-cell analysis; vivo morpholino