Distinct adhesion-independent functions of β-catenin control stage-specific sensory neurogenesis and proliferation

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.

Tcf7l1 protects the anterior neural fold from adopting the neural crest fate

“…This indicates the AP2α-Cre driver to be a more suitable tool for studying early events of NC development. Our data provide evidence for an earlier role of the Wnt/β-catenin pathway in NC development than evident from previously published findings in the mouse model showing the requirement for the Wnt/β-catenin pathway in NC maintenance and differentiation (Brault et al, 2001;Gay et al, 2015;Lee et al, 2004).…”

“…The widely used Wnt1-Cre mouse targets the NC population after its induction and specification (Danielian et al, 1998;Lewis et al, 2013). Depletion of β-catenin using Wnt1-Cre leads to malformations of the craniofacial structures, accompanied with a deficiency in sensory neurons (Brault et al, 2001;Gay et al, 2015). Similar phenotypic changes have been observed in compound Wnt1/Wnt3a mutants, which also show impaired formation of sensory neurons and defects in several bones and cartilage derived from the NC (Ikeya et al, 1997).…”

Wnt/Fgf crosstalk is required for the specification of tracheal basal progenitor cells

“…Taken together these results suggest that the cellular adhesion function of ß-catenin plays roles in tracheal development. That being said, we can't rule out the possibility that some residual ß-catenin mediated transcription regulation activities remain present in Shh-Cre;Ctnnb1 DM/loxp mutants, even though TCF-transactivation dependent Wnt signaling is ablated in various studies using the Ctnnb1 DM mouse line (Azim et al, 2014;Gay et al, 2015;Valenta et al, 2016;Valenta et al, 2011).…”

“…This mutant form of βcatenin includes a single amino acid change (aspartic acid mutated to Alanine, D164A) in the first Armadillo repeat of β-catenin, which prevents TCF-dependent transcription regulation while maintaining the ability to mediate cellular adhesion (Valenta et al, 2011). Notably, Ctnnb1 DM/DM mutants die at E10.5 (Gay et al, 2015). We combined this allele with the Ctnnb1 loxp allele to address whether ß-catenin acts in the epithelium to regulate basal cell development.…”

Chemical Disruption of Wnt-dependent Cell Fate Decision-making Mechanisms in Cancer and Regenerative Medicine

“…Some evidence that chemical disruption of β-catenin transcriptional activity will differ in phenotypic outcome from studies using engineered animals that express a β-catenin lacking signaling activity but retains cell-cell adhesion functions [19, 20]. When also considered with the essential roles of Tnks enzymes in development and the often time overlapping function of the two homologous enzymes [21], Tnks inhibitors should be valuable probes for understanding β-catenin in adult tissues that bypasses several limitations of genetic approaches.…”