The on/off of Pax6 controls the tempo of neuronal differentiation in the developing spinal cord.
During neurogenesis, complex networks of genes act sequentially to control neuronal differentiation. In the neural tube, the expression of Pax6, a paired-box-containing gene, just precedes the appearance of the first post-mitotic neurons. So far, its only reported function in the spinal cord is in specifying subsets of neurons. Here we address its possible function in controlling the balance between proliferation and commitment of neural progenitors. We report that increasing Pax6 level is sufficient to push neural progenitors toward cell cycle exit and neuronal commitment via Neurogenin 2 (Ngn2) upregulation. However, neuronal precursors maintaining Pax6(On) fail to perform neuronal differentiation. Conversely, turning off Pax6 function in these precursors is sufficient to provoke premature differentiation and the number of differentiated neurons depends of the amount of Pax6 protein. Moreover, we found that Pax6 expression involves negative feedback regulation by Ngn2 and this repression is critical for the proneural activity of Ngn2. We present a model in which the level of Pax6 activity first conditions the moment when a given progenitor will leave the cell cycle and second, the moment when a selected neuronal precursor will irreversibly differentiate.
Bel-Vialar
Sophie
S
Centre de Biologie du Développement, CNRS UMR5547 Bât 4R3, Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 09, France. belviala@cict.fr
Medevielle
François
F
Pituello
Fabienne
F
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002642:Chick Embryo; D005136:Eye Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013997:Time Factors
D051792:Basic Helix-Loop-Helix Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; C102938:Neurog2 protein, mouse; C000605732:Pax6 protein, mouse