LEF-1, a Nuclear Factor Coordinating Signaling Inputs from wingless and decapentaplegic

Abstract

wingless and decapentaplegic signal during endoderm induction in Drosophila to regulate expression of the homeotic gene Ultrabithorax. Here, we define a minimal wingless response sequence in the midgut enhancer of Ultrabithorax. We show that this sequence is recognized by the murine transcription factor LEF-1 (lymphocyte enhancer binding factor 1) in a ternary complex with armadillo protein, the cytoplasmic target of the wingless signaling pathway. In stable transformants, transcriptional stimulation of the Ultrabithorax enhancer by LEF-1 depends on armadillo. Furthermore, overexpression of LEF-1 bypasses the need for wingless signaling and causes phenotypes in the midgut, notum, and wing that mimic wingless hyperstimulation. Finally, efficient transcriptional stimulation by LEF-1 in the midgut depends also on the decapentaplegic response sequence and is limited spatially by decapentaplegic signaling. Thus, LEF-1 coordinates inputs from multiple positional signals, consistent with its architectural role in regulating the assembly of multiprotein enhancer complexes.

Transgenic Wnt/TCF pathway reporters: all you need is Lef?

“…The first test of multimerized T-cell factor (TCF) sites in vivo was performed in Drosophila (Riese et al, 1997). Four copies of a TCF binding site, taken from a Wntregulated midgut enhancer of the Ultrabithorax (Ubx) gene, were placed upstream of a minimal TATAcontaining promoter driving lacZ.…”

“…Four copies of a TCF binding site, taken from a Wntregulated midgut enhancer of the Ultrabithorax (Ubx) gene, were placed upstream of a minimal TATAcontaining promoter driving lacZ. This binding site is necessary for Wnt-mediated activation of the Ubx enhancer in vivo (Riese et al, 1997;Yu et al, 1998). However, transgenic flies carrying the multimerized TCF site reporter construct showed no lacZ expression in Wnt-responding cells, even upon overexpression of the Wingless ligand (Riese et al, 1997).…”

“…This binding site is necessary for Wnt-mediated activation of the Ubx enhancer in vivo (Riese et al, 1997;Yu et al, 1998). However, transgenic flies carrying the multimerized TCF site reporter construct showed no lacZ expression in Wnt-responding cells, even upon overexpression of the Wingless ligand (Riese et al, 1997). On the same day that this result appeared in Cell, a report in Science introduced TOPFLASH, a luciferase-expressing transfection construct, containing multimerized 'optimal' TCF binding sites, that responds specifically to Wnt/ b-catenin pathway stimulation in cultured cells (Korinek et al, 1997).…”

“…However, before placing strong interpretations on the observed presence or absence of reporter expression in a given cell type, it is worth noting that these reporters are not infallible. In the mouse, close comparisons of different TCF reporters have revealed discrepancies in certain contexts, such as in the node and primitive streak of the early embryo, in the follicle matrix and dermal papillae cells of developing hair follicles, and in the adult brain ( (Riese et al, 1997;Geng et al, 2003;Dessimoz et al, 2005;Fathke et al, 2006). These observations suggest that evidence derived from TCF reporters regarding the presence or absence of Wnt/b-catenin signaling in a given tissue should not be regarded as conclusive in itself.…”

Bio-sketch for Oncogene Review Issue on Wnt signalling

“…This marked the beginning of her interest in the molecular mechanisms of Wnt signal transduction. She pinpointed the Wingless-responsive element within the midgut enhancer from the homeotic gene Ultrabithorax, and demonstrated that TCF/LEF factors acted through this element to mediate the Wingless response (Riese et al, 1997). Soon after this, the critical role of the Wnt signalling pathway in cancer began to emerge.…”