The role of Phox2b in synchronizing pan-neuronal and type-specific aspects of neurogenesis

Development. 2002 Nov;129(22):5241-53.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Differentiation / physiology
  • Chick Embryo
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Eye Proteins
  • Gene Expression Regulation, Developmental
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Inhibitor of Differentiation Protein 2
  • LIM-Homeodomain Proteins
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neural Crest / cytology
  • Neural Crest / embryology*
  • Neural Crest / metabolism*
  • Oligodendrocyte Transcription Factor 2
  • PAX6 Transcription Factor
  • Paired Box Transcription Factors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Stem Cells / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Up-Regulation
  • Zebrafish Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Eye Proteins
  • Hes5 protein, mouse
  • Homeodomain Proteins
  • Inhibitor of Differentiation Protein 2
  • LIM-Homeodomain Proteins
  • NBPhox protein
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • Nkx2.2 protein
  • Nkx6-1 protein, mouse
  • Nkx6.2 protein, vertebrate
  • Olig2 protein, mouse
  • Oligodendrocyte Transcription Factor 2
  • PAX6 Transcription Factor
  • PAX6 protein, human
  • Paired Box Transcription Factors
  • Pax6 protein, mouse
  • Repressor Proteins
  • Transcription Factors
  • Zebrafish Proteins
  • insulin gene enhancer binding protein Isl-1
  • HES5 protein, human