Six3 represses nodal activity to establish early brain asymmetry in zebrafish.
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.
Department of Biological Sciences, Vanderbilt University, VU Station B 351634, Nashville, TN 37235-1634, USA.
Adi
A
Inbal
Seok-Hyung
SH
Kim
Jimann
J
Shin
Lilianna
L
Solnica-Krezel
D000818:Animals; D001921:Brain / Q000196:embryology*; D004292:Dominance, Cerebral / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology*; D004843:Epistasis, Genetic; D019261:Epithalamus / Q000196:embryology; D005136:Eye Proteins / Q000502:physiology*; D018398:Homeodomain Proteins / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D055457:Nodal Protein; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D000097607:Homeobox Protein SIX3
D005136:Eye Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D055457:Nodal Protein; D016212:Transforming Growth Factor beta; D000097607:Homeobox Protein SIX3; C526007:NODAL protein, human