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Links between signal transduction, transcription and adhesion in epithelial bud development

Nature volume 422, pages 317–322 (2003)Cite this article

An Erratum to this article was published on 21 August 2003

Abstract

The morphogenesis of organs as diverse as lungs, teeth and hair follicles is initiated by a downgrowth from a layer of epithelial stem cells1,2. 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 β-catenin, and a bone morphogenetic protein (BMP) inhibitor to produce Lef1. β-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 dynamics3. 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.

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Figure 1: Wnt and noggin induce a transcriptionally competent Lef1 complex that is absent in Nog-/- mice.
Figure 2: During follicle morphogenesis and cycling, skin stem cells change cadherin expression in a fashion dependent upon noggin and Wnt signalling.
Figure 3: Lef1 and β-catenin transcriptionally downregulate E-cadherin in vitro.
Figure 4: Levels of adherens junction proteins influence follicle morphogenesis.

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Acknowledgements

We thank L. Degenstein and J. Fan for transgenic technology; B. Merrill and M. Perez-Moreno for comments on the manuscript; W. Lowry and H. Rhee for sharing experimental expertise; M. Takeichi and R. Burgeson for antibodies; A. McMahon and R. Grosschedl for knockout mice; R. Kemler, A. Garcia de Herreros and H. Clevers for cDNAs and vectors; R. Harland and S. Takada for cell lines. C.J. is supported by the Helen Hay Whitney foundation. R.D. was a graduate student at the University of Chicago, where a portion of this work was conducted. This work was supported by the National Institutes of Health.

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  1. Ramanuj DasGupta

    Present address: Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA

Authors and Affiliations

  1. Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York, 10021, USA

    Colin Jamora, Ramanuj DasGupta, Pawel Kocieniewski & Elaine Fuchs

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Correspondence to Elaine Fuchs.

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Jamora, C., DasGupta, R., Kocieniewski, P. et al. Links between signal transduction, transcription and adhesion in epithelial bud development. Nature 422, 317–322 (2003). https://doi.org/10.1038/nature01458

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