Zebrafish hdac1 reciprocally regulates the canonical and non-canonical Wnt pathways

Wnt proteins comprise a large family of secreted glycoproteins that regulate key developmental processes including cell proliferation, cell polarity and cell fate determination. The Wnt signaling machinery is tightly regulated and disruption of components of the signaling pathway have been implicated in diseases including cancer. The 'canonical' Wnt/[beta]-catenin signaling pathway links Wnt signaling to stabilization of the [beta]-catenin protein and regulates pattering and cell fate specification. Wnt signaling can also initiate an independent 'non-canonical' pathway that regulates developmental events involved in planar cell polarity and convergent extension movements via small GTPases and JNK kinase. My study involves the characterization of the zebrafish mutant colgate (col) which displays defects in early dorsal fate and anterior neural fate specification as well as defects in the extension of the body axis. I have identified hdac1 as the gene encoded by col. Using molecular, genetic and phenotypic analysis I propose that hdac1 acts as a modulator of both canonical and non-canonical wnt signaling. Blocking excess canonical Wnt signaling in col mutants by overexpressing antagonists or by injecting antisense morpholino oligonucleotides directed against canonical Wnt ligands rescued the dorso-ventral and anterior neural patterning defects. Strikingly, these embryos still retained defects in body axis extension. Activation of the non-canonical Wnt pathway in col mutant embryos rescued the extension defects without affecting aberrant patterning phenotypes. My data suggests a role for col/hdac1 both as an antagonist of the canonical Wnt pathway and as an activator of the non-canonical Wnt signaling pathway. Furthermore, we show that col/hdac1 genetically interacts with vangl2 to regulate the caudal migration of the nVII facial hindbrain branchiomotor neurons via a pathway independent of the non-canonical Wnt pathway. Although previous studies have shown that hdac1 functions as a corepressor of the canonical Wnt pathway, my studies indicate for the first time that hdac1 functions to promote early dorsal fates and participates in patterning the developing neuroectoderm. My work also provides evidence for a novel role of hdac1 as an activator of the non-canonical Wnt pathway in addition to repressing the Wnt/[beta]-catenin signaling pathway.