title: Post-translational Control of the Temporal Dynamics of Transcription Factor Activity Regulates Neurogenesis.
abstract: Neurogenesis is initiated by the transient expression of the highly conserved proneural proteins, bHLH transcriptional regulators. Here, we discover a conserved post-translational switch governing the duration of proneural protein activity that is required for proper neuronal development. Phosphorylation of a single Serine at the same position in Scute and Atonal proneural proteins governs the transition from active to inactive forms by regulating DNA binding. The equivalent Neurogenin2 Threonine also regulates DNA binding and proneural activity in the developing mammalian neocortex. Using genome editing in Drosophila, we show that Atonal outlives its mRNA but is inactivated by phosphorylation. Inhibiting the phosphorylation of the conserved proneural Serine causes quantitative changes in expression dynamics and target gene expression resulting in neuronal number and fate defects. Strikingly, even a subtle change from Serine to Threonine appears to shift the duration of Atonal activity in vivo, resulting in neuronal fate defects.
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Quan
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium; Program in Molecular and Developmental Genetics, Doctoral School for Biomedical Sciences, University of Leuven School Group Biomedicine, 3000 Leuven, Belgium.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Welbio, Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 1070 Brussels, Belgium.
authors.forename: Luca
authors.initials: L
authors.lastname: Tiberi
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Claeys
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: De Geest
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Jiekun
authors.initials: J
authors.lastname: Yan
authors.affiliation: VIB Switch Laboratory, 3000 Leuven, Belgium; Department for Cellular and Molecular Medicine, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Rob
authors.initials: R
authors.lastname: van der Kant
authors.affiliation: Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Wei R
authors.initials: WR
authors.lastname: Xie
authors.affiliation: Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Tiemo J
authors.initials: TJ
authors.lastname: Klisch
authors.affiliation: VIB Switch Laboratory, 3000 Leuven, Belgium; Department for Cellular and Molecular Medicine, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Joost
authors.initials: J
authors.lastname: Shymkowitz
authors.affiliation: VIB Switch Laboratory, 3000 Leuven, Belgium; Department for Cellular and Molecular Medicine, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
authors.affiliation: Laboratory of Biosignaling and Therapeutics, Department of Cellular and Molecular Medicine, University of Leuven School of Medicine, 3000 Leuven, Belgium.
authors.forename: Monique
authors.initials: M
authors.lastname: Beullens
authors.affiliation: Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium; Welbio, Université Libre de Bruxelles (ULB), Institute for Interdisciplinary Research (IRIBHM), and ULB Institute of Neuroscience (UNI), 1070 Brussels, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vanderhaeghen
authors.affiliation: VIB Center for the Biology of Disease, VIB, 3000 Leuven, Belgium; Center for Human Genetics, University of Leuven School of Medicine, 3000 Leuven, Belgium; Program in Molecular and Developmental Genetics, Doctoral School for Biomedical Sciences, University of Leuven School Group Biomedicine, 3000 Leuven, Belgium. Electronic address: bassem.hassan@icm-institute.org.
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Hassan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins; D005123:Eye / Q000254:growth & development / Q000648:ultrastructure; D060227:Imaginal Discs / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis; D010766:Phosphorylation; D012160:Retina / Q000254:growth & development; D016415:Sequence Alignment
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; C082142:ato protein, Drosophila