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Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/β-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of β-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features.

Background: Mouse genetic study has demonstrated that Axin2 is essential for calvarial development and disease. Haploid deficiency of β-catenin alleviates the calvarial phenotype caused by Axin2 deficiency. This loss-of-function study provides evidence for the requirement of β-catenin in exerting the downstream effects of Axin2. Results: Here we utilize a gain-of-function analysis to further assess the role of β-catenin. A transgenic expression system permitting conditional activation of β-catenin in a spatiotemporal specific manner has been developed. Aberrant stimulation of β-catenin leads to increases in expansion of skeletogenic precursors and the enhancement of bone ossification reminiscent to the loss of Axin2. The constitutively active signal promotes specification of osteoprogenitors, but prevents their maturation into terminally differentiated osteoblasts, along the osteoblast lineage. However, the prevention does not interfere with bone synthesis, suggesting that mineralization occurs without the presence of mature osteoblasts. β-catenin signaling apparently plays a key role in suture development through modulation of calvarial morphogenetic signaling pathways. Furthermore, genetic inactivation of the β-catenin transcriptional target, cyclin D1, impairs expansion of the skeletogenic precursors contributing to deficiencies in calvarial ossification. There is a specific requirement for cyclin D1 in populating osteoprogenitor cell types at various developmental stages. Conclusion: These findings advance our knowledge base of Wnt signaling in calvarial morphogenesis, suggesting a key regulatory pathway of Axin2/β-catenin/cyclin D1 in development of the suture mesenchyme. [ABSTRACT FROM AUTHOR]

Members of the Wnt family are secreted glycoproteins that trigger cellular signals essential for proper development of organisms. Cellular signaling induced by Wnt proteins is involved in diverse developmental processes and human diseases. Previous studies have generated an enormous wealth of knowledge on the events in signal-receiving cells. However, relatively little is known about the making of Wnt in signal-producing cells. Here, we describe that Gpr177, the mouse orthologue of Drosophila Wis, is expressed during formation of embryonic axes. Embryos with deficient Gpr177 exhibit defects in establishment of the body axis, a phenotype highly reminiscent to the loss of Wnt3. Although many different mammalian Wnt proteins are required for a wide range of developmental processes, the Wnt3 ablation exhibits the earliest developmental abnormality. This suggests that the Gpr177-mediated Wnt production cannot be substituted. As a directtarget of Wnt, Gpr177 is activated by β-catenin and LEF/TCF-dependent transcription. This activation alters the cellular distributions of Gpr177 which binds to Wnt proteins and assists their sorting and secretion in a feedback regulatory mechanism. Our findings demonstrate that the loss of Gpr177 affects Wnt production in the signal-producing cells, leading to alterations of Wnt signaling in the signal-receiving cells. A reciprocal regulation of Wnt and Gpr177 is essential for the patterning of the anterior-posterior axis during mammalian development [ABSTRACT FROM AUTHOR]

We have developed an advanced method for conditional gene expression in mice that integrates the Cre-mediated and tetra- cycline-dependent expression systems. An rtTA gene, preceded by a loxP-flanked STOP sequence, was inserted into the ROSA26 locus to create a R26STOPrtTA mouse strain. When the STOP sequence is excised by Cre-mediated recombination, the rtTA is expressed in the Cre-expressing cells and all of their derivatives Therefore, cell type-, tissue-, or lineage-specific expression of rtTA is achieved by the use of an appropriate Cre transgenic strain. In mice also carrying a target gene under the control of the tetracycline response element, inducible expression of the target gene is temporally regulated by administration of doxycycline. Our results demonstrate that this universal system is uniquely suited for spatiotemporal and lineage-specific gene expression in an inducible fashion. Gene expression can be manipulated in specific cell types and lineages with a flexibility that is difficult to achieve with conventional methods. [ABSTRACT FROM AUTHOR]