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
