Reciprocal gene replacements reveal unique functions for Phox2 genes during neural differentiation

EMBO J. 2005 Dec 21;24(24):4392-403. doi: 10.1038/sj.emboj.7600897. Epub 2005 Dec 1.


The paralogous paired-like homeobox genes Phox2a and Phox2b are involved in the development of specific neural subtypes in the central and peripheral nervous systems. The different phenotypes of Phox2 knockout mutants, together with their asynchronous onset of expression, prompted us to generate two knock-in mutant mice, in which Phox2a is replaced by the Phox2b coding sequence, and vice versa. Our results indicate that Phox2a and Phox2b are not functionally equivalent, as only Phox2b can fulfill the role of Phox2a in the structures that depend on both genes. Furthermore, we demonstrate unique roles of Phox2 genes in the differentiation of specific motor neurons. Whereas the oculomotor and the trochlear neurons require Phox2a for their proper development, the migration of the facial branchiomotor neurons depends on Phox2b. Therefore, our analysis strongly indicates that biochemical differences between the proteins rather than temporal regulation of their expression account for the specific function of each paralogue.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Differentiation
  • Cell Movement
  • DNA, Complementary / metabolism
  • Ganglia / metabolism
  • Gene Expression Regulation*
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology*
  • Homozygote
  • Immunohistochemistry
  • In Situ Hybridization
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Genetic
  • Motor Neurons / metabolism
  • Mutation
  • Neurons / metabolism*
  • Oculomotor Nerve / metabolism
  • Phenotype
  • Protein Binding
  • Recombinant Proteins / metabolism
  • Time Factors
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Trochlear Nerve / metabolism
  • beta-Galactosidase / metabolism


  • DNA, Complementary
  • Homeodomain Proteins
  • NBPhox protein
  • Phox2a protein, mouse
  • Recombinant Proteins
  • Transcription Factors
  • beta-Galactosidase