title: Villification in the mouse: Bmp signals control intestinal villus patterning.
abstract: In the intestine, finger-like villi provide abundant surface area for nutrient absorption. During murine villus development, epithelial Hedgehog (Hh) signals promote aggregation of subepithelial mesenchymal clusters that drive villus emergence. Clusters arise first dorsally and proximally and spread over the entire intestine within 24 h, but the mechanism driving this pattern in the murine intestine is unknown. In chick, the driver of cluster pattern is tensile force from developing smooth muscle, which generates deep longitudinal epithelial folds that locally concentrate the Hh signal, promoting localized expression of cluster genes. By contrast, we show that in mouse, muscle-induced epithelial folding does not occur and artificial deformation of the epithelium does not determine the pattern of clusters or villi. In intestinal explants, modulation of Bmp signaling alters the spatial distribution of clusters and changes the pattern of emerging villi. Increasing Bmp signaling abolishes cluster formation, whereas inhibiting Bmp signaling leads to merged clusters. These dynamic changes in cluster pattern are faithfully simulated by a mathematical model of a Turing field in which an inhibitor of Bmp signaling acts as the Turing activator. In vivo, genetic interruption of Bmp signal reception in either epithelium or mesenchyme reveals that Bmp signaling in Hh-responsive mesenchymal cells controls cluster pattern. Thus, unlike in chick, the murine villus patterning system is independent of muscle-induced epithelial deformation. Rather, a complex cocktail of Bmps and Bmp signal modulators secreted from mesenchymal clusters determines the pattern of villi in a manner that mimics the spread of a self-organizing Turing field.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA kdwalton@med.umich.edu dgumucio@med.umich.edu.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Walton
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Whidden
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Instituet, Novum, Huddinge SE-141 83, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Kolterud
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
authors.forename: Suzanne K
authors.initials: SK
authors.lastname: Shoffner
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Czerwinski
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Juhi
authors.initials: J
authors.lastname: Kushwaha
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Nishita
authors.initials: N
authors.lastname: Parmar
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Chandhrasekhar
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Freddo
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
authors.forename: Santiago
authors.initials: S
authors.lastname: Schnell
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA kdwalton@med.umich.edu dgumucio@med.umich.edu.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Gumucio
mesh_terms: D000818:Animals; D019521:Body Patterning; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D004848:Epithelium / Q000196:embryology; D053823:Hedgehog Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D007422:Intestines / Q000196:embryology*; D008024:Ligands; D008648:Mesoderm / Q000196:embryology; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000378:metabolism*; D008954:Models, Biological; D009130:Muscle, Smooth / Q000196:embryology; D009929:Organ Size; D015398:Signal Transduction; D013718:Tensile Strength
chemical_list: D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D008024:Ligands; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Activator-inhibitor patterning model; Epithelial-mesenchymal crosstalk; Intestinal development; Mathematical model; Morphogenesis; Turing field; Villus formation