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GSK3beta inactivation leads to Repression of Gbx2 expression
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|GSK3beta inactivation leading to increased mortality via defects in developing inner ear||adjacent||Moderate||Low||Vid Modic (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Wnt signaling is implicated in anteroposterior (AP) axis patterning and midbrain specification in both animal and human systems. GSK3 is a key enzyme mediating the canonical Wnt signaling. Inhibition of GSK3b (one of the isoforms of GSK3) leads to activation of canonical Wnt signal pathway (Grassilli et al., 2014). Gbx2 is one of the representative AP markers and is downregulated in activation of Wnt signal pathway (GSK3b inhibition) (Kim et al., 2018).
Evidence Supporting this KER
- Zebrafish embryos were treated with chemical inhibitors or activators of various signaling pathways, such as the Wnt, FGF, retinoic acid (RA), HH, BMP, Nodal, and Notch pathways, from 14 hpf to 18 hpf, immediately before the advent of gbx2 expression in the telencephalon, and than gbx2 expression was examined in the telencephalon. In zebrafish embryos treated with BIO, a selective GSK3 inhibitor that activates Wnt signaling, gbx2 expression was specifically repressed in the telencephalon, but was unaffected or weakly activated in the isthmus and OV (Wang et al., 2018).
- Treatment of human ESC-derived NCPs with BIO (Gsk3b inhibitor) downregulated expression of GBX2 in dose dependent manner (Kim et al., 2018). Quantitative gene expression analysis following seven days of treatment revealed that the GBX2 expression decreased as the BIO concentration increased (Kim et al., 2018).
- To confirm whether the effect of BIO on midbrain specification was indeed through the activation of canonical Wnt signal, other small molecules that inhibit GSK3 were tested in different modes of action, such as 1- AKP and LiCl on human ESC-derived NPCs. LiCl treatment elicited similar gene expression patterns (decreased expression of GBX2) as BIO treatment, although the fold changes in gene expression were lower than those of the other inhibitors. These data support that midbrain-specific gene expression results from the activation of canonical Wnt signal via GSK3 inhibition (Kim et al., 2018).
Uncertainties and Inconsistencies
Gbx2 begins to express in telencephalon approximately 14-18hpf (Wang et al., 2018).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Evidence for this KER is provided for zebrafish (Wang et al., 2018) and humans (Grassilli et al., 2014; Kim et al., 2018).
Grassilli, E. et al. (2014) ‘GSK3A is redundant with GSK3B in modulating drug resistance and chemotherapy-induced necroptosis’, PLoS ONE, 9(7), pp. 1–8. doi: 10.1371/journal.pone.0100947.
Kim, J. Y. et al. (2018) ‘Wnt signal activation induces midbrain specification through direct binding of the beta-catenin/TCF4 complex to the EN1 promoter in human pluripotent stem cells’, Experimental & Molecular Medicine, 50, p. 24. doi: 10.1038/s12276-018-0044-y.
Wang, Z. et al. (2018) ‘The role of gastrulation brain homeobox 2 (gbx2) in the development of the ventral telencephalon in zebrafish embryos’, Differentiation, 99(December 2017), pp. 28–40. doi: 10.1016/j.diff.2017.12.005.