Lophotrochozoan Zic Genes
5.6 Summary of the Lophotrochozoan Zic Genes
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In previous studies, Wnt signaling was shown to play a key role in head regenera- tion. Functional interaction between zic1 and wnt signaling was further investigated by combining β-catenin (wnt canonical pathway component) knockdown and zic1 knockdown (Fig. 5.6f). When β-catenin was solely suppressed in the trunk pieces, ectopic head regeneration occurred from the posterior side, consistent with its key role in head regeneration. zic1 suppression causes the loss of head structure and intact tail as above. But the combined knockdown treatment abolished the zic1 effect, identical to β-catenin knockdown animals (Fig. 5.6f). This result indicates that β-catenin inhibition can promote head regeneration in the absence of zic1, sug- gesting a critical role of β-catenin inhibition in zic1-mediated head regeneration (Fig. 5.6e).
Besides the components of Wnt signaling, other candidate genes were examined to determine their requirements for zic1 expression activation after amputation.
Follistatin knockdown resulted in the reduction of the zic1-expressing cells at 24 h after amputation. FoxD knockdown resulted in the reduction of zic1 expression 3 days after amputation (Vogg et al. 2014). In addition, Pbx1 (homeodomain tran- scription factor) knockdown also reduced the number of zic1-expressing cells and zic1 expression levels 24 days after amputation.
Based on these two studies, the role of planarian Zic in head regeneration can be summarized as below (Fig. 5.6e). At the anterior side of the wounds, zic1 expression in the stem cells (neoblast) is induced by the secretory wnt signaling inhibitor (notum).
zic1 in the stem cells is necessary for the wnt signaling inhibitor and TGFβ (activin) signaling antagonist (follistatin). The anterior-most zic1-expressing stem cells are called anterior pole cells and also express the winged helix-type transcription factor foxD. zic1 and foxD cooperate to establish the anterior pole cell properties.
The method of zic1 involvement in planarian head regeneration is intriguing when compared with the involvement of vertebrate Zic family in the repression of Wnt-β-catenin signaling (Fujimi et al. 2012; Pourebrahim et al. 2011). Xenopus Zic3 suppresses β-catenin signaling to control the organizer, which emanates TGFβ (BMP) signaling antagonists (chordin, follistatin, etc.) (Fujimi et al. 2012). On the other hand, the CNS disorganization caused by planarian zic1 RNAi is similar to brain abnormalities in holoprosencephaly patients caused by ZIC2 loss-of-function mutations (Brown et al. 1998) and in Zic2 knockdown mutant mice (Nagai et al.
2000). In either case, the midline region of the “brain” is impaired. Despite such phenotypic similarities, planarian head regeneration may provide a promising experimental system to clarify the evolutionary conserved gene regulatory network for brain establishment.
ancestral characteristics. Furthermore, their possible involvement in novel lophotro- chozoan (chaetal sac-associated mesoderm derivative) development and the essen- tial role of planarian Zic genes in head regeneration were found based on lophotrochozoan model animals. In addition, Zic in dicyemids, secondarily reduced lophotrochozoans, may shed new light on gametogenesis, a metazoan core develop- mental process that has not been fully addressed in conventional animal models with complex traits (e.g., muscle and nervous system).
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