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.
Inbal
Adi
A
Department of Biological Sciences, Vanderbilt University, VU Station B 351634, Nashville, TN 37235-1634, USA.
Kim
Seok-Hyung
SH
Shin
Jimann
J
Solnica-Krezel
Lilianna
L
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