Abstract
The morphogenesis of organs as diverse as lungs, teeth and hair follicles is initiated by a downgrowth from a layer of epithelial stem cells. During follicular morphogenesis, stem cells form this bud structure by changing their polarity and cell-cell contacts. Here we show that this process is achieved through simultaneous receipt of two external signals: a Wnt protein to stabilize beta-catenin, and a bone morphogenetic protein (BMP) inhibitor to produce Lef1. Beta-catenin then binds to, and activates, Lef1 transcription complexes that appear to act uncharacteristically by downregulating the gene encoding E-cadherin, an important component of polarity and intercellular adhesion. When either signal is missing, functional Lef1 complexes are not made, and E-cadherin downregulation and follicle morphogenesis are impaired. In Drosophila, E-cadherin can influence the plane of cell division and cytoskeletal dynamics. Consistent with this notion, we show that forced elevation of E-cadherin levels block invagination and follicle production. Our findings reveal an intricate molecular programme that links two extracellular signalling pathways to the formation of a nuclear transcription factor that acts on target genes to remodel cellular junctions and permit follicle formation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adherens Junctions / metabolism
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Animals
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Bone Morphogenetic Proteins / genetics
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Bone Morphogenetic Proteins / metabolism
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Cadherins / genetics
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Cadherins / metabolism*
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Carrier Proteins
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Cell Adhesion
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Cytoskeletal Proteins / metabolism
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Epithelial Cells / cytology*
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Epithelial Cells / metabolism*
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Gene Deletion
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Gene Expression Regulation, Developmental
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Hair Follicle / cytology
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Hair Follicle / embryology*
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Hair Follicle / metabolism*
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In Situ Hybridization
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Mice
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Mice, Knockout
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Mice, Transgenic
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Morphogenesis
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Signal Transduction*
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Stem Cells / cytology
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Stem Cells / metabolism
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Trans-Activators / metabolism
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Transcription Factors / metabolism
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Transcription, Genetic*
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Wnt Proteins
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Zebrafish Proteins*
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beta Catenin
Substances
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Bone Morphogenetic Proteins
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CTNNB1 protein, mouse
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Cadherins
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Carrier Proteins
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Lef1 protein, mouse
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Trans-Activators
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Transcription Factors
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Wnt Proteins
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Zebrafish Proteins
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beta Catenin
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noggin protein