ABSTRACT
Fungiform taste papillae form a regular array on the dorsal tongue. Taste buds arise from papilla epithelium and, unusually for epithelial derivatives, synapse with neurons, release neurotransmitters and generate receptor and action potentials. Despite the importance of taste as one of our five senses, genetic analyses of taste papilla and bud development are lacking. We demonstrate that Wnt-beta-catenin signaling is activated in developing fungiform placodes and taste bud cells. A dominant stabilizing mutation of epithelial beta-catenin causes massive overproduction of enlarged fungiform papillae and taste buds. Likewise, genetic deletion of epithelial beta-catenin or inhibition of Wnt-beta-catenin signaling by ectopic dickkopf1 (Dkk1) blocks initiation of fungiform papilla morphogenesis. Ectopic papillae are innervated in the stabilizing beta-catenin mutant, whereas ectopic Dkk1 causes absence of lingual epithelial innervation. Thus, Wnt-beta-catenin signaling is critical for fungiform papilla and taste bud development. Altered regulation of this pathway may underlie evolutionary changes in taste papilla patterning.
Subject(s)
Taste Buds/embryology , Wnt Proteins/physiology , beta Catenin/physiology , Animals , Animals, Newborn , Cells, Cultured , Female , Intercellular Signaling Peptides and Proteins/genetics , Mice , Mice, Transgenic , Morphogenesis/genetics , Pregnancy , Signal Transduction/genetics , Taste Buds/growth & development , beta Catenin/geneticsABSTRACT
Embryonic hair follicle development and postnatal hair growth rely on intercellular communication within the epithelium and between epithelial and mesenchymal cells. Several members of the WNT family of paracrine intercellular signaling molecules are expressed in specific subsets of cells in developing and mature mouse hair follicles, suggesting them as candidates for some of the intercellular signals that operate in these organs. As WNT ligands activate several different signaling pathways, they may play multiple and complex roles in developing and postnatal skin. To begin to investigate these functions, we have used in situ hybridization to identify cells that express Frizzled (Fz) WNT receptor genes, and so are potentially receptive to WNT ligands. We find that several Fz genes are specifically expressed at sites of known activity of the WNT/beta-catenin signaling pathway, allowing us to identify candidate receptors for canonical WNT ligands important in appendage development. The expression of additional Fz genes is specifically elevated at locations and developmental stages other than those that display WNT/beta-catenin pathway activity, suggesting that signaling through alternate WNT pathways may contribute to the development and function of skin and hair.
Subject(s)
Hair Follicle/embryology , Hair Follicle/physiology , Proteins/genetics , Receptors, Neurotransmitter/genetics , Age Factors , Animals , Cell Division/physiology , Cytoskeletal Proteins/metabolism , Female , Frizzled Receptors , Gene Expression Regulation, Developmental , Hair Follicle/cytology , Mice , Mice, Inbred BALB C , Pregnancy , Proto-Oncogene Proteins/metabolism , Receptors, Cell Surface , Receptors, G-Protein-Coupled/genetics , Trans-Activators/metabolism , Wnt Proteins , beta CateninABSTRACT
Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles.
Subject(s)
Hair Follicle/growth & development , Hair/growth & development , Morphogenesis/genetics , Osteogenesis/physiology , Protein Serine-Threonine Kinases/physiology , Receptors, Growth Factor/physiology , Animals , Bone Morphogenetic Protein Receptors, Type I , Cell Differentiation , Cell Division , Epidermis/embryology , Female , Hair Follicle/cytology , In Situ Hybridization , Integrases/genetics , Lactation , Mice , Mice, Inbred Strains , Mice, Transgenic , Viral Proteins/geneticsABSTRACT
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.
