A Wnt signaling control mechanisms known for cancer cells regulates Wnt signaling activity and links neural network function and mental disorder.
Figure: Premature intrinsic activation of Wnt signaling delays habenular neuron differentiation. (A-B′) Dorsal views onto the zebrafish brain, anterior is towards the top. Nuclei are labeled in purple, developing neurons are green. (A,A′,C) Transient Wnt signaling activation using lithium chloride (LiCl) causes a specific loss of GFP-expressing habenular neurons. (B,B′,D,E) The number of differentiating habenular neurons is reduced but their left-right asymmetric development remains unchanged. CTRL, control; Hb,habenulae; P, pineal; Tec, optic tectum; Th, thalamus (modified after Guglielmi et al., 2020).
Anatomical left-right asymmetries are common to all vertebrates and even some invertebrates analysed to date. The Wnt signaling pathway has been shown to influence the development of these differences in the brain. A study published by Luca Guglielmi now shows that the timing of this pathway's activity is crucially important. Premature activation delays neuron differentiation and results in the symmetry of the otherwise left-right asymmetrically developing habenular structure. The central player in this process is the Wnt inhibitory factor Wif1, which blocks any Wnt signaling activating molecules and protects habenular precursor cells. This work by Guglielmi and colleagues is particularly interesting on various levels: Luca found that Wif1 acts in a regulatory feedback loop with Wnt, which enables the system to react quickly to environmental changes regarding Wnt signals. This phenomenon has been postulated already for cancer cells and hence seems a common mechanism for influencing cell fates.
Secondly, the Wif1 gene had been previously identified as a potential risk gene for autism. As the habenular neural network in humans has been equally linked to this disorder, it is tempting to speculate that Luca has discovered a novel prove linking habenular network, Wif1 gene and mental disorder.
Publication:
Guglielmi, L., Bühler, A., Moro, E., Argenton, F., Poggi, L. and Carl, M. (2020). Temporal control of Wnt signaling is required for habenular neuron diversity and brain asymmetry (2020). Development, 147(6):dev.182865.