Slit/Robo signaling modulates the proliferation of central nervous system progenitors.
Neurogenesis relies on a delicate balance between progenitor maintenance and neuronal production. Progenitors divide symmetrically to increase the pool of dividing cells. Subsequently, they divide asymmetrically to self-renew and produce new neurons or, in some brain regions, intermediate progenitor cells (IPCs). Here we report that central nervous system progenitors express Robo1 and Robo2, receptors for Slit proteins that regulate axon guidance, and that absence of these receptors or their ligands leads to loss of ventricular mitoses. Conversely, production of IPCs is enhanced in Robo1/2 and Slit1/2 mutants, suggesting that Slit/Robo signaling modulates the transition between primary and intermediate progenitors. Unexpectedly, these defects do not lead to transient overproduction of neurons, probably because supernumerary IPCs fail to detach from the ventricular lining and cycle very slowly. At the molecular level, the role of Slit/Robo in progenitor cells involves transcriptional activation of the Notch effector Hes1. These findings demonstrate that Robo signaling modulates progenitor cell dynamics in the developing brain.
Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant 03550, Spain. vborrell@umh.es
Víctor
V
Borrell
Adrián
A
Cárdenas
Gabriele
G
Ciceri
Joan
J
Galcerán
Nuria
N
Flames
Ramón
R
Pla
Sandrina
S
Nóbrega-Pereira
Cristina
C
García-Frigola
Sandra
S
Peregrín
Zhen
Z
Zhao
Le
L
Ma
Marc
M
Tessier-Lavigne
Oscar
O
Marín
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology* / Q000196:embryology; D016009:Chi-Square Distribution; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019579:Neocortex / Q000166:cytology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D000072056:Transcription Factor HES-1; D014162:Transfection; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000072056:Transcription Factor HES-1; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C489734:Hes1 protein, mouse; C498888:Robo2 protein, mouse; C120010:Slit1 protein, mouse