Abstract
Backgroundβ-catenin plays a central role in multiple developmental processes. However, it has been difficult to study its pleiotropic effects, because of the dual capacity of β-catenin to coordinate cadherin-dependent cell adhesion and to act as a component of Wnt signal transduction. To distinguish between the divergent functions of β-catenin during peripheral nervous system development, we made use of a mutant allele of β-catenin that can mediate adhesion but not Wnt-induced TCF transcriptional activation. This allele was combined with various conditional inactivation approaches.ResultsWe show that of all peripheral nervous system structures, only sensory dorsal root ganglia require β-catenin for proper formation and growth. Surprisingly, however, dorsal root ganglia development is independent of cadherin-mediated cell adhesion. Rather, both progenitor cell proliferation and fate specification are controlled by β-catenin signaling. These can be divided into temporally sequential processes, each of which depends on a different function of β-catenin.ConclusionsWhile early stage proliferation and specific Neurog2- and Krox20-dependent waves of neuronal subtype specification involve activation of TCF transcription, late stage progenitor proliferation and Neurog1-marked sensory neurogenesis are regulated by a function of β-catenin independent of TCF activation and adhesion. Thus, switching modes of β-catenin function are associated with consecutive cell fate specification and stage-specific progenitor proliferation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0134-4) contains supplementary material, which is available to authorized users.
Highlights
Canonical Wnt signaling is one of the most important evolutionarily conserved signaling pathways in embryonic development [1,2,3]
(See figure on previous page.) Figure 1 Total loss of β-catenin leads to a more severe phenotype in the dorsal root ganglia than inhibition of the TCF/Lef transcriptional output of β-catenin. (A) The β-catenin protein consists of 12 Armadillo repeats, a conserved helix-C (C), an amino-terminal domain (NTD), and a carboxy-terminal domain (CTD) [15]
It links transmembrane cadherins via α-catenin to the actin cytoskeleton. (B”) β-catenin-dm inhibits TCF/Lef-mediated transcription, but preserves cadherin-mediated adhesion. (B”’) Cells of βcat-Null animals lose both TCF/Lef-mediated transcription and cadherin-mediated adhesion. (C’-C”’) In vivo fate mapping of Wnt1-Cre embryos carrying the ROSA26 Cre reporter line (R26R) reporter allele at E12.5. (D) Illustration of a transverse section of an E12.5 control animal displaying in red the neural derivatives of neural crest cells: dorsal root ganglia (DRG); sympathetic ganglia (SG); enteric nervous system (ENS)
Summary
Canonical Wnt signaling is one of the most important evolutionarily conserved signaling pathways in embryonic development [1,2,3]. Transmembrane cadherins bind to the first eleven Armadillo repeats of β-catenin, while actin-bound α-catenin binds to the amino-terminal domain This dual role of β-catenin in mediating Wnt signaling and cell-cell adhesion made it difficult to collate a specific phenotype obtained upon β-catenin gene (Ctnnb1) manipulation to either or both functions of β-catenin. A dominant negative effect of the mutated protein can be excluded as heterozygous animals carrying Ctnnb1dm display no phenotype [15] This form of βcatenin has a single amino acid change in the first Armadillo repeat of β-catenin (D164A), which prevents the binding of the N-terminal transcriptional co-activators BCL9/BCL9L. Β-catenin-dm maintains the ability to mediate cellular adhesion and, likely, to de-repress TCF targets, allowing the identification of effects of β-catenin that are TCF-transactivation independent
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