title: Robo1 modulates proliferation and neurogenesis in the developing neocortex.
abstract: The elaborate cytoarchitecture of the mammalian neocortex requires the timely production of its constituent pyramidal neurons and interneurons and their disposition in appropriate layers. Numerous chemotropic factors present in the forebrain throughout cortical development play important roles in the orchestration of these events. The Roundabout (Robo) family of receptors and their ligands, the Slit proteins, are expressed in the developing forebrain, and are known to play important roles in the generation and migration of cortical interneurons. However, few studies have investigated their function(s) in the development of pyramidal cells. Here, we observed expression of Robo1 and Slit genes (Slit1, Slit2) in cells lining the telencephalic ventricles, and found significant increases in progenitor cells (basal and apical) at embryonic day (E)12.5 and E14.5 in the developing cortex of Robo1(-/-), Slit1(-/-), and Slit1(-/-)/Slit2(-/-), but not in mice lacking the other Robo or Slit genes. Using layer-specific markers, we found that both early- and late-born pyramidal neuron populations were significantly increased in the cortices of Robo1(-/-) mice at the end of corticogenesis (E18.5). The excess number of cortical pyramidal neurons generated prenatally appears to die in early postnatal life. The observed increase in pyramidal neurons was due to prolonged proliferative activity of their progenitors and not due to changes in cell cycle events. This finding, confirmed by in utero electroporation with Robo1 short hairpin RNA (shRNA) or control constructs into progenitors along the ventricular zone as well as in dissociated cortical cell cultures, points to a novel role for Robo1 in regulating the proliferation and generation of pyramidal neurons.
authors.affiliation: Department of Cell and Developmental Biology, University College London, London, United Kingdom WC1E 6DE, Laboratory for Neocortical Development, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, Institut Jacques-Monod, Université Paris Diderot/CNRS, 75201 Paris, France, and Institut de la Vision, INSERM UMRS 968, F75012 Paris, France.
authors.forename: Mason L
authors.initials: ML
authors.lastname: Yeh
authors.forename: Yuko
authors.initials: Y
authors.lastname: Gonda
authors.forename: Mathilda T M
authors.initials: MT
authors.lastname: Mommersteeg
authors.forename: Melissa
authors.initials: M
authors.lastname: Barber
authors.forename: Athena R
authors.initials: AR
authors.lastname: Ypsilanti
authors.forename: Carina
authors.initials: C
authors.lastname: Hanashima
authors.forename: John G
authors.initials: JG
authors.lastname: Parnavelas
authors.forename: William D
authors.initials: WD
authors.lastname: Andrews
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins
keywords: Robo; corticogenesis; progenitors; proliferation
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