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A Wif1 mediated feedback loop suppresses premature Wnt signaling in nascent habenular neurons
Precise temporal and spatial control of cell signaling processes is pivotal for embryonic development. A vast number of secreted signaling molecules such as Wnt ligands travel between cells and tissues and influence their fate. If they are to induce a signaling cascade depends on various control mechanisms of potential target cells. These can include the temporal expression control of pathway components or the generation of signaling agonisers or antagonisers. Control of Wnt/beta-catenin signaling is important for the establishment of left- rigt (l-r) neuronal asymmetries of the evolutionarily conserved habenulae in the vertebrate dorsal diencephalon. During neurogenesis, this pathway is activated only when habenular precursor cells become post-mitotic, although Wnt ligands secreted by the adjacent mid-diencephalic organizer (MDO) surround these cells much earlier. The underlying control mechanism and its purpose have remained unexplored. We find that Wnt signaling is indeed initially inhibited in habenular precursors and that this is required for habenular neurons to subsequently adopt different neuronal fates. Indeed, premature induction of the pathway critically delays neuronal differentiation which ultimately lead to precursor differentiation into only one out of two neuron types of the habenulae on both sides of the brain. We further show that the early activation of Wnt signaling is naturally prevented by Wnt inhibitor factor 1 (Wif1), which is specifically expressed in the habenulae until precursors become post-mitotic. Suppression of wif1 phenocopies the effect of early Wnt induction. Furthermore, wif1 expression is positively regulated by Wnt signaling showing that wif1 is functioning within a negative feedback loop. Our data are consistent with a model by which Wif1 dynamically shields early multipotent habenular precursor cells from incoming Wnt ligands secreted by the MDO and possibly other the sources until they become post-mitotic and differentiate into neurons. wif1 and different Wnt ligands are overlappingly expressed in a number of developing structures including both the habenulae the downstream target the interpenduncular nucleus (IPN). This suggests that the Wnt/Wif1 buffering system may serve as a general mechanism for temporally tuning neurogenesis across the different nuclei of the brain.
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