Evidence that embryonic neurons regulate the onset of cortical gliogenesis via cardiotrophin-1.
Precursor cells of the embryonic cortex sequentially generate neurons and then glial cells, but the mechanisms regulating this neurogenic-to-gliogenic transition are unclear. Using cortical precursor cultures, which temporally mimic this in vivo differentiation pattern, we demonstrate that cortical neurons synthesize and secrete the neurotrophic cytokine cardiotrophin-1, which activates the gp130-JAK-STAT pathway and is essential for the timed genesis of astrocytes in vitro. Our data indicate that a similar phenomenon also occurs in vivo. In utero electroporation of neurotrophic cytokines in the environment of embryonic cortical precursors causes premature gliogenesis, while acute perturbation of gp130 in cortical precursors delays the normal timed appearance of astrocytes. Moreover, the neonatal cardiotrophin-1-/- cortex contains fewer astrocytes. Together, these results describe a neural feedback mechanism; newly born neurons produce cardiotrophin-1, which instructs multipotent cortical precursors to generate astrocytes, thereby ensuring that gliogenesis does not occur until neurogenesis is largely complete.
Barnabé-Heider
Fanie
F
Developmental Biology, University of Toronto, Toronto M5G 1X8, Canada.
Wasylnka
Julie A
JA
Fernandes
Karl J L
KJ
Porsche
Christian
C
Sendtner
Michael
M
Kaplan
David R
DR
Miller
Freda D
FD
D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D058966:Contactins; D017077:Culture Media, Conditioned / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D016207:Cytokines / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D004347:Drug Interactions; D051959:ELAV Proteins / Q000378:metabolism; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D015850:Interleukin-6 / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000378:metabolism; D053605:Leukemia Inhibitory Factor; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D038081:Organogenesis; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014404:Tubulin / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D020934:Ciliary Neurotrophic Factor; D058966:Contactins; D017077:Culture Media, Conditioned; D016207:Cytokines; D051959:ELAV Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005904:Glial Fibrillary Acidic Protein; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D007381:Intermediate Filament Proteins; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D019006:Neural Cell Adhesion Molecules; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D050791:STAT Transcription Factors; D014404:Tubulin; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C462941:beta3 tubulin, mouse; C061195:neurofilament protein M; D049452:Green Fluorescent Proteins; C092073:cardiotrophin 1; D011505:Protein-Tyrosine Kinases; D051357:Cyclin-Dependent Kinase 2; D010751:Phosphopyruvate Hydratase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one