Editors' ChoiceWnt signaling

One Transgene: Two Outcomes

Science's STKE  30 Jul 2002:
Vol. 2002, Issue 143, pp. tw276-TW276
DOI: 10.1126/stke.2002.143.tw276

Wnt signaling leads to the stabilization of β-catenin, which then acts as a transcriptional activator in concert with the transcription factor TCF/LEF. In skin, activation of this signaling pathway promotes hair follicle cell fate. DasGupta et al. used a transgenic mouse model expressing a COOH-terminally truncated version of β-catenin that lacked the DNA binding domain to study cell fate specification in mouse skin (ΔNΔCβ-catenin). (The construct also lacked the NH2-terminal region and so was stabilized and not subject to the normal β-catenin degradation pathway.) They found that this ΔNΔCβ-catenin acted as a dominant negative in the cells that form the hair follicle, converting these into an epidermal cell type and promoting the formation of a cyst instead of a hair follicle. Analysis of promoter activity using mice carrying a TCF/LEF-responsive reporter showed that in the mice expressing ΔNΔCβ-catenin, the precursor hair cells did not activate the TCF/LEF reporter. In a subset of cells closer to the skin surface, the ΔNΔCβ-catenin acted as a gain-of-function mutation with the formation of abnormal flowerlike structures in the epidermis that eventually formed hair cell tumors. The cells at the base of these structures had intense TCF/LEF reporter gene expression, suggesting activation of the Wnt pathway. Using cultured primary cells from the transgenic animals, the authors found that in keratinocytes stimulated to differentiate by the addition of calcium, endogenous β-catenin was stabilized and localized to the nucleus in the cells, consistent with a positive effect of ΔNΔCβ-catenin on Wnt signaling. In the epidermal cysts formed instead of normal hair follicles, the ratio of ΔNΔCβ-catenin to endogenous β-catenin was high, consistent with the inhibitory effect of ΔNΔCβ-catenin on Wnt signaling. Thus, β-catenin signaling is different in these cells, possibly reflecting differences in the abundance of interacting factors.

R. DasGupta, H. Rhee, E. Fuchs, A developmental conundrum: a stabilized form of β-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells. J. Cell. Biol. 158, 331-344 (2002). [Abstract] [Full Text]