title: SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland.
abstract: SHARPIN is a widely expressed multifunctional protein implicated in cancer, inflammation, linear ubiquitination and integrin activity inhibition; however, its contribution to epithelial homeostasis remains poorly understood. Here, we examined the role of SHARPIN in mammary gland development, a process strongly regulated by epithelial-stromal interactions. Mice lacking SHARPIN expression in all cells (Sharpincpdm), and mice with a stromal (S100a4-Cre) deletion of Sharpin, have reduced mammary ductal outgrowth during puberty. In contrast, Sharpincpdmmammary epithelial cells transplanted in vivo into wild-type stroma, fully repopulate the mammary gland fat pad, undergo unperturbed ductal outgrowth and terminal differentiation. Thus, SHARPIN is required in mammary gland stroma during development. Accordingly, stroma adjacent to invading mammary ducts of Sharpincpdmmice displayed reduced collagen arrangement and extracellular matrix (ECM) stiffness. Moreover, Sharpincpdmmammary gland stromal fibroblasts demonstrated defects in collagen fibre assembly, collagen contraction and degradation in vitro Together, these data imply that SHARPIN regulates the normal invasive mammary gland branching morphogenesis in an epithelial cell extrinsic manner by controlling the organisation of the stromal ECM.
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland emilia.peuhu@utu.fi johanna.ivaska@utu.fi.
authors.forename: Emilia
authors.identifier: 0000-0003-4945-3046
authors.initials: E
authors.lastname: Peuhu
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Riina
authors.initials: R
authors.lastname: Kaukonen
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Martina
authors.initials: M
authors.lastname: Lerche
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Saari
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Camilo
authors.initials: C
authors.lastname: Guzmán
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Pia
authors.identifier: 0000-0003-1638-5075
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Franceschi
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Wärri
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Georgiadou
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jacquemet
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Mattila
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Virtakoivu
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin at Madison, Madison, WI, USA.
authors.forename: Yuming
authors.identifier: 0000-0001-5391-8892
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.
authors.forename: Youmna
authors.initials: Y
authors.lastname: Attieh
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Silva
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.|Center for Molecular Biology of Inflammation, Cells-in-Motion Cluster of Excellence, Institute of Cell Biology, Münster University, Münster, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Betz
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.affiliation: MediCity Research Laboratory, University of Turku, Turku, Finland.|Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, Paris, France.|Institut Curie, CNRS, UMR144, Paris, France.
authors.forename: Marie-Ange
authors.initials: MA
authors.lastname: Deugnier
authors.affiliation: Department of Biomedical Engineering, Laboratory for Optical and Computational Instrumentation (LOCI), University of Wisconsin at Madison, Madison, WI, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Eliceiri
authors.affiliation: Centre for Biotechnology, University of Turku, Turku, Finland emilia.peuhu@utu.fi johanna.ivaska@utu.fi.|Department of Biochemistry and Food Chemistry, University of Turku, Turku, Finland.
authors.forename: Johanna
authors.identifier: 0000-0002-6295-6556
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042361:Mammary Glands, Human / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C554944:Sipl1 protein, mouse; D003094:Collagen
keywords: 
  SHARPIN
  ; collagen; ductal morphogenesis; fibroblast; mammary gland