Barhl2 limits growth of the diencephalic primordium through Caspase3 inhibition of beta-catenin activation
Hugo A. Juraver-Geslin, Jérome J. Ausseil, Marion Wassef, and Béatrice C. Durand
Little is known about the respective contributions of cell pro- liferation and cell death to the control of vertebrate fore- brain growth. The homeodomain protein barhl2 is expressed in the diencephalons of Xenopus, zebrafish, and mouse embryos, and we previously showed that Barhl2 overexpression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. Here, barhl2 is shown to act as a brake on diencephalic proliferation through an unconventional function of Caspase3. Depletion of Barhl2 or Caspase3 causes an increase in diencephalic cell number, a disruption of the neuroepithelium architecture, and an increase in Wnt activity. Surprisingly, these changes are not caused by de- creased apoptosis but instead, are because of an increase in the amount and activation of β-catenin, which stimulates excessive neu- roepithelial cell proliferation and induces defects in β-catenin intra- cellular localization and an up-regulation of axin2 and cyclinD1, two downstream targets of β-catenin/T-cell factor/lymphoïd enhancer factor signaling. Using two different sets of complementation experiments, we showed that, in the developing diencephalon, Caspase3 acts downstream of Barhl2 in limiting neuroepithelial cell proliferation by inhibiting β-catenin activation. Our data argue that Bar homeodomain proteins share a conserved function as cell type- specific regulators of Caspase3 activities.
Proc Natl Acad Sci U S A. 2011 Feb 8 ;108(6):2288-93
