The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis.
Within the developing vertebrate nervous system, specific subclasses of neurons are produced in vastly different numbers at defined times and locations. This implies the concomitant activation of a program that controls pan-neuronal differentiation and of a program that specifies neuronal subtype identity, but how these programs are coordinated in time and space is not well understood. Our previous loss- and gain-of-function studies have defined Phox2b as a homeodomain transcription factor that coordinately regulates generic and type-specific neuronal properties. It is necessary and sufficient to impose differentiation towards a branchio- and viscero-motoneuronal phenotype and at the same time promotes generic neuronal differentiation. We have examined the underlying genetic interactions. We show that Phox2b has a dual action on pan-neuronal differentiation. It upregulates the expression of proneural genes (Ngn2) when expressed alone and upregulates the expression of Mash1 when expressed in combination with Nkx2.2. By a separate pathway, Phox2b represses expression of the inhibitors of neurogenesis Hes5 and Id2. The role of Phox2b in the specification of neuronal subtype identity appears to depend in part on its capacity to act as a patterning gene in the progenitor domain. Phox2b misexpression represses the Pax6 and Olig2 genes, which should inhibit a branchiomotor fate, and induces Nkx6.1 and Nkx6.2, which are expressed in branchiomotor progenitors. We further show that Phox2b behaves like a transcriptional activator in the promotion of both, generic neuronal differentiation and expression of the motoneuronal marker Islet1. These results provide insights into the mechanisms by which a homeodomain transcription factor through interaction with other factors controls both generic and type-specific features of neuronal differentiation.
Dubreuil
Véronique
V
CNRS UMR 8542, Département de Biologie, Ecole Normale Supérieure, 46, rue d'Ulm, 75230 Paris Cedex 05, France.
Hirsch
Marie-Rose
MR
Jouve
Caroline
C
Brunet
Jean-François
JF
Goridis
Christo
C
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000502:physiology; D002642:Chick Embryo; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins; D018507:Gene Expression Regulation, Developmental; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051797:Inhibitor of Differentiation Protein 2; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009432:Neural Crest / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D005136:Eye Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D051797:Inhibitor of Differentiation Protein 2; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; C489685:Hes5 protein, mouse; C109220:NBPhox protein; C491183:NEUROG2 protein, human; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; C491328:Nkx6-1 protein, mouse; C436827:Nkx6.2 protein, vertebrate; C512773:Olig2 protein, mouse; C000605730:PAX6 protein, human; C000605732:Pax6 protein, mouse; C063843:insulin gene enhancer binding protein Isl-1; C000715630:nkx2.2b protein, zebrafish; C077478:HES5 protein, human