Laminar patterning in the developing neocortex by temporally coordinated fibroblast growth factor signaling.
Laminar organization, a fundamental neural architecture in the CNS, is a prominent feature of the neocortex, where the cortical neurons in spatially distinct layers are generated from the common progenitors in a temporally distinct manner during development. Despite many advances in the characterization of the molecular mechanisms of the radial migration of cortical neurons, the way in which the early-late temporal sequence of cortical neuron generation is linked with the deep-superficial spatial sequence of cell body positioning remains obscure. Using in vivo electroporation-mediated gene transfer, we show here that the activities mediated by fibroblast growth factor receptors (FGFRs) in cortical progenitors are critical for conferring proper migratory properties on nascent neuronal progeny. Furthermore, we provide supportive evidence that Pea3 subfamily members of Ets (Pea3-Ets) transcription factors mediate the activities of FGFR at the mid to late phase of neocortical development. In addition, using FGF18 knock-out mice, we demonstrate that FGF18 expressed by early-generated cortical neurons in the cortical plate is critical for the expression of Pea3-Ets transcription factors and that FGF18 is sufficient to induce their expressions. Our results thus imply that a feedback mechanism mediated by FGF signaling is involved in setting up the proper laminar positioning of cortical neurons; FGF18 derived from early-generated cortical neurons acts on the cortical progenitors expressing FGFRs and induces the expression of Pea3-Ets transcription factors that, in turn, confer proper migratory behaviors on nascent cortical progeny during the mid to late stages of neocortical development.
Neural Organization Research Team, Mitsubishi Kagaku Institute of Life Sciences, Precursory Research for Embryonic Science and Technology, Japan Science and Technology, Machida, Tokyo, Japan.
Hiroshi
H
Hasegawa
Shizuko
S
Ashigaki
Masako
M
Takamatsu
Rika
R
Suzuki-Migishima
Norihiko
N
Ohbayashi
Nobuyuki
N
Itoh
Shinji
S
Takada
Yasuto
Y
Tanabe
D000818:Animals; D019521:Body Patterning; D002465:Cell Movement; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D007700:Kinetics; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009154:Mutation; D019579:Neocortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; C113569:fibroblast growth factor 18; C065788:transcription factor PEA3; D005346:Fibroblast Growth Factors; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3