Abstract
Brain regionalisation, neuronal subtype diversification and circuit connectivity are crucial events in the establishment of higher cognitive functions. Here we report the requirement for the transcriptional repressor Fezf2 for proper differentiation of neural progenitor cells during the development of the Xenopus forebrain. Depletion of Fezf2 induces apoptosis in postmitotic neural progenitors, with concomitant reduction in forebrain size and neuronal differentiation. Mechanistically, we found that Fezf2 stimulates neuronal differentiation by promoting Wnt/β-catenin signalling in the developing forebrain. In addition, we show that Fezf2 promotes activation of Wnt/β-catenin signalling by repressing the expression of two negative regulators of Wnt signalling, namely lhx2 and lhx9. Our findings suggest that Fezf2 plays an essential role in controlling when and where neuronal differentiation occurs within the developing forebrain and that it does so by promoting local Wnt/β-catenin signalling via a double-repressor model.
Highlights
The vertebrate forebrain, which carries out higher neural functions, is a highly organised and complex structure derived from the anteriormost region of the neural plate
We have identified fezf2 as a positive regulator of Wnt/β-catenin signalling in the rostral forebrain, and we have revealed the molecular mechanism by which fezf2 triggers Wnt signalling and consequent neural progenitor differentiation and forebrain growth in the Xenopus embryo
We show that fezf2 promotes Wnt/βcatenin signalling at the differentiation stage, and that this activity is required for proper development of the forebrain
Summary
The vertebrate forebrain, which carries out higher neural functions, is a highly organised and complex structure derived from the anteriormost region of the neural plate. Transgenic embryos expressing the Wnt-agonising ΔN90β-catenin construct demonstrated expansion of arx staining, excessive growth of differentiated neural tissue, and enlarged eyes, suggesting that elevated Wnt activity promotes the growth of neural tissue within the forebrain (Juraver-Geslin et al, 2011) (Fig. 3Dc,c′,E; supplementary material Fig. S6Dc). These results confirmed that the antimorphic Fezf acts as a negative regulator of Wnt signalling, and that proper Wnt signalling in fezf2-expressing areas is crucial for normal forebrain development in vivo. These findings suggest that fezf inhibits the expression of the Wnt-repressive transcription factors lhx and lhx, promoting ngn expression and, subsequently, neurogenesis in the forebrain
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