title: Reciprocal autoregulation by NFI occupancy and ETV1 promotes the developmental expression of dendrite-synapse genes in cerebellar granule neurons.
abstract: Nuclear Factor One (NFI) transcription factors regulate temporal gene expression required for dendritogenesis and synaptogenesis via delayed occupancy of target promoters in developing cerebellar granule neurons (CGNs). Mechanisms that promote NFI temporal occupancy have not been previously defined. We show here that the transcription factor ETV1 directly binds to and is required for expression and NFI occupancy of a cohort of NFI-dependent genes in CGNs maturing in vivo. Expression of ETV1 is low in early postnatal cerebellum and increases with maturation, mirroring NFI temporal occupancy of coregulated target genes. Precocious expression of ETV1 in mouse CGNs accelerated onset of expression and NFI temporal occupancy of late target genes and enhanced Map2(+) neurite outgrowth. ETV1 also activated expression and NFI occupancy of the Etv1 gene itself, and this autoregulatory loop preceded ETV1 binding and activation of other coregulated target genes in vivo. These findings suggest a potential model in which ETV1 activates NFI temporal binding to a subset of late-expressed genes in a stepwise manner by initial positive feedback regulation of the Etv1 gene itself followed by activation of downstream coregulated targets as ETV1 expression increases. Sequential transcription factor autoregulation and subsequent binding to downstream promoters may provide an intrinsic developmental timer for dendrite/synapse gene expression.
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Baojin
authors.initials: B
authors.lastname: Ding
authors.affiliation: Burke Medical Research Institute, White Plains, NY 10605 Weill Cornell Medical College, Brain and Mind Research Institute, New York, NY 10065.
authors.forename: John W
authors.initials: JW
authors.lastname: Cave
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Dobner
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Debra
authors.initials: D
authors.lastname: Mullikin-Kilpatrick
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Marina
authors.initials: M
authors.lastname: Bartzokis
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Chi-Wing
authors.initials: CW
authors.lastname: Chow
authors.affiliation: Department of Biochemistry, Program in Neuroscience and Developmental Genomics Group, New York State Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY 14203.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gronostajski
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Neuroscience, University of Massachusetts Medical School, Worcester, MA 01605 Daniel.kilpatrick@umassmed.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kilpatrick
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D003712:Dendrites / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D062211:Spatio-Temporal Analysis; D013569:Synapses / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C490641:Etv1 protein, mouse; D051839:NFI Transcription Factors; D014157:Transcription Factors