WNTs: multiple genes, multiple functions.
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Biomedical subjects
Sarah E Millar
Publications and source records attributed to Sarah E Millar.
The WNT7b promoter is regulated by TTF-1, GATA6, and Foxa2 in lung epithelium.
In this study, we find that WNT7b is the only member of the WNT family of autocrine/paracrine signaling molecules whose expression in the lung is restricted to the airway epithelium during embryonic development. To study the transcriptional mechanisms that underlie this restricted pattern of WNT7b expression, we isolated the proximal 1.0-kb mouse WNT7b promoter and mapped the transcriptional start sites. Transfection of the lung epithelial cell line MLE-15, which expresses WNT7b, shows that the 1.0-kb mouse WNT7b promoter is highly active in lung epithelial cells. This region of the WNT7b promoter contains several DNA binding sites for the important lung-restricted transcription factors TTF-1, GATA6, and Foxa2. Electrophoretic mobility shift assays showed that TTF-1, GATA6, and Foxa2 can bind to a specific subset of their consensus DNA binding sites within the WNT7b promoter. Using cotransfection assays, we demonstrate that TTF-1, GATA6, and Foxa2 can trans-activate the WNT7b promoter in NIH-3T3 cells. Truncation of GATA6 or Foxa2 binding sites reduced the ability of these transcriptional regulators to trans-activate the WNT7b promoter. Finally, the minimal 118-bp region of the mouse WNT7b promoter containing only TTF-1 binding sites was synergistically activated by TTF-1 and GATA6, and we show that TTF-1 and GATA6 physically interact in vivo. Together, these results suggest that WNT7b gene expression in the lung epithelium is regulated in a combinatorial fashion by TTF-1, GATA6, and Foxa2.
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WNT signals are required for the initiation of hair follicle development.
Hair follicle morphogenesis is initiated by a dermal signal that induces the development of placodes in the overlying epithelium. To determine whether WNT signals are required for initiation of follicular development, we ectopically expressed Dickkopf 1, a potent diffusible inhibitor of WNT action, in the skin of transgenic mice. This produced a complete failure of placode formation prior to morphological or molecular signs of differentiation, and blocked tooth and mammary gland development before the bud stage. This phenotype indicates that activation of WNT signaling in the skin precedes, and is required for, localized expression of regulatory genes and initiation of hair follicle placode formation.
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Molecular mechanisms regulating hair follicle development.
Clinical conditions causing hair loss, such as androgenetic alopecia, alopecia areata, and scarring alopecia, can be psychologically devastating to individuals and are the target of a multimillion dollar pharmaceutical industry. The importance of the hair follicle in skin biology, however, does not rest solely with its ability to produce hair. Hair follicles are self-renewing and contain reservoirs of multipotent stem cells that are capable of regenerating the epidermis and are thought to be utilized in wound healing. Hair follicles are also the sites of origin of many neoplasias, including some basal cell carcinomas and pilomatricoma. These diseases result from inappropriate activation of signaling pathways that regulate hair follicle morphogenesis. Identification of the signaling molecules and pathways operating in developing and postnatal, cycling, hair follicles is therefore vital to our understanding of pathogenic states in the skin and may ultimately permit the development of novel therapies for skin tumors as well as for hair loss disease. The purpose of this review is to summarize recent progress in our understanding of the molecular mechanisms regulating hair follicle formation, and to discuss ways in which this information may eventually be utilized in the clinic.
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