title: Scratch2 modulates neurogenesis and cell migration through antagonism of bHLH proteins in the developing neocortex.
abstract: Scratch genes (Scrt) are neural-specific zinc-finger transcription factors (TFs) with an unknown function in the developing brain. Here, we show that, in addition to the reported expression of mammalian Scrt2 in postmitotic differentiating and mature neurons in the developing and early postnatal brain, Scrt2 is also localized in subsets of mitotic and neurogenic radial glial (RGP) and intermediate (IP) progenitors, as well as in their descendants-postmitotic IPs and differentiating neurons at the border subventricular/intermediate zone. Conditional activation of transgenic Scrt2 in cortical progenitors in mice promotes neuronal differentiation by favoring the direct mode of neurogenesis of RGPs at the onset of neurogenesis, at the expense of IP generation. Neuronal amplification via indirect IP neurogenesis is thereby extenuated, leading to a mild postnatal reduction of cortical thickness. Forced in vivo overexpression of Scrt2 suppressed the generation of IPs from RGPs and caused a delay in the radial migration of upper layer neurons toward the cortical plate. Mechanistically, our results indicate that Scrt2 negatively regulates the transcriptional activation of the basic helix loop helix TFs Ngn2/NeuroD1 on E-box containing common target genes, including Rnd2, a well-known major effector for migrational defects in developing cortex. Altogether, these findings reveal a modulatory role of Scrt2 protein in cortical neurogenesis and neuronal migration.
authors.affiliation: Research Group Molecular Developmental Neurobiology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Paul
authors.forename: Anton B
authors.initials: AB
authors.lastname: Tonchev
authors.forename: Kristine A
authors.initials: KA
authors.lastname: Henningfeld
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pavlakis
authors.forename: Barbara
authors.initials: B
authors.lastname: Rust
authors.forename: Tomas
authors.initials: T
authors.lastname: Pieler
authors.forename: Anastassia
authors.initials: A
authors.lastname: Stoykova
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D001616:beta-Galactosidase; D000099260:Empty Spiracles Homeobox Proteins; C000591999:SCRATCH2 protein, mouse