Hox Proteins Drive Cell Segregation and Non-Autonomous Apical Remodelling During Hindbrain Segmentation

Development. 2014 Apr;141(7):1492-502. doi: 10.1242/dev.098954. Epub 2014 Feb 26.


Hox genes encode a conserved family of homeodomain transcription factors regulating development along the major body axis. During embryogenesis, Hox proteins are expressed in segment-specific patterns and control numerous different segment-specific cell fates. It has been unclear, however, whether Hox proteins drive the epithelial cell segregation mechanism that is thought to initiate the segmentation process. Here, we investigate the role of vertebrate Hox proteins during the partitioning of the developing hindbrain into lineage-restricted units called rhombomeres. Loss-of-function mutants and ectopic expression assays reveal that Hoxb4 and its paralogue Hoxd4 are necessary and sufficient for cell segregation, and for the most caudal rhombomere boundary (r6/r7). Hox4 proteins regulate Eph/ephrins and other cell-surface proteins, and can function in a non-cell-autonomous manner to induce apical cell enlargement on both sides of their expression border. Similarly, other Hox proteins expressed at more rostral rhombomere interfaces can also regulate Eph/ephrins, induce apical remodelling and drive cell segregation in ectopic expression assays. However, Krox20, a key segmentation factor expressed in odd rhombomeres (r3 and r5), can largely override Hox proteins at the level of regulation of a cell surface target, Epha4. This study suggests that most, if not all, Hox proteins share a common potential to induce cell segregation but in some contexts this is masked or modulated by other transcription factors.

Keywords: Apical polarity; Cell affinities; Cell segregation; Cell sorting; Cell tension; Chick; Hindbrain; Hox; Mouse; Rhombomeres; Segmentation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Body Patterning / genetics*
  • Cell Movement / genetics*
  • Chick Embryo
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Genes, Homeobox / physiology
  • Homeodomain Proteins / physiology*
  • Membrane Proteins / genetics
  • Mice
  • Rhombencephalon / embryology*
  • Rhombencephalon / metabolism
  • Transcription Factors / physiology


  • Homeodomain Proteins
  • Hoxb4 protein, mouse
  • Hoxd4 protein, mouse
  • Membrane Proteins
  • Transcription Factors