Requirement of multiple basic helix-loop-helix genes for retinal neuronal subtype specification

J Biol Chem. 2004 Jul 2;279(27):28492-8. doi: 10.1074/jbc.M400871200. Epub 2004 Apr 22.


Retinal precursor cells give rise to six types of neurons and one type of glial cell during development, and this process is controlled by multiple basic helix-loop-helix (bHLH) genes. However, the precise mechanism for specification of retinal neuronal subtypes, particularly horizontal neurons and photoreceptors, remains to be determined. Here, we examined retinas with three different combinations of triple bHLH gene mutations. In retinas lacking the bHLH genes Ngn2, Math3, and NeuroD, horizontal neurons as well as other neurons such as bipolar cells were severely decreased in number. In the retina lacking the bHLH genes Mash1, Ngn2, and Math3, horizontal and other neurons were severely decreased, whereas ganglion cells were increased. In the retina lacking the bHLH genes Mash1, Math3, and NeuroD, photoreceptors were severely decreased, whereas ganglion cells were increased. In all cases, glial cells were increased. The increase and decrease of these cells were the result of cell fate changes and cell death and seem to be partly attributable to the remaining bHLH gene expression, which also changes because of triple bHLH gene mutations. These results indicate that multiple bHLH genes cross-regulate each other, cooperatively specify neuronal subtypes, and regulate neuronal survival in the developing retina.

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Death
  • Cell Lineage
  • Cell Survival
  • DNA-Binding Proteins / genetics
  • Helix-Loop-Helix Motifs
  • Immunohistochemistry
  • In Situ Hybridization
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Neurons / metabolism*
  • Retina / metabolism*
  • Time Factors
  • Transcription Factors / genetics


  • Ascl1 protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • NEUROG2 protein, human
  • Nerve Tissue Proteins
  • Neurod4 protein, mouse
  • Neurog2 protein, mouse
  • Transcription Factors
  • Neurogenic differentiation factor 1