Six3 represses nodal activity to establish early brain asymmetry in zebrafish

Neuron. 2007 Aug 2;55(3):407-15. doi: 10.1016/j.neuron.2007.06.037.


The vertebrate brain is anatomically and functionally asymmetric; however, the molecular mechanisms that establish left-right brain patterning are largely unknown. In zebrafish, asymmetric left-sided Nodal signaling within the developing dorsal diencephalon is required for determining the direction of epithalamic asymmetries. Here, we show that Six3, a transcription factor essential for forebrain formation and associated with holoprosencephaly in humans, regulates diencephalic Nodal activity during initial establishment of brain asymmetry. Reduction of Six3 function causes brain-specific deregulation of Nodal pathway activity, resulting in epithalamic laterality defects. Based on misexpression and genetic epistasis experiments, we propose that Six3 acts in the neuroectoderm to establish a prepattern of bilateral repression of Nodal activity. Subsequently, Nodal signaling from the left lateral plate mesoderm alleviates this repression ipsilaterally. Our data reveal a Six3-dependent mechanism for establishment of correct brain laterality and provide an entry point to understanding the genetic regulation of Nodal signaling in the brain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology*
  • Dominance, Cerebral / physiology*
  • Embryonic Development / physiology*
  • Epistasis, Genetic
  • Epithalamus / embryology
  • Eye Proteins / physiology*
  • Homeodomain Proteins / physiology*
  • Nerve Tissue Proteins / physiology*
  • Nodal Protein
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Zebrafish / embryology*
  • Zebrafish / genetics


  • Eye Proteins
  • Homeodomain Proteins
  • NODAL protein, human
  • Nerve Tissue Proteins
  • Nodal Protein
  • Sine oculis homeobox homolog 3 protein
  • Transforming Growth Factor beta