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  • SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland.

SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland.

The EMBO journal (2016-12-16)
Emilia Peuhu, Riina Kaukonen, Martina Lerche, Markku Saari, Camilo Guzmán, Pia Rantakari, Nicola De Franceschi, Anni Wärri, Maria Georgiadou, Guillaume Jacquemet, Elina Mattila, Reetta Virtakoivu, Yuming Liu, Youmna Attieh, Kathleen A Silva, Timo Betz, John P Sundberg, Marko Salmi, Marie-Ange Deugnier, Kevin W Eliceiri, Johanna Ivaska
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, Sharpincpdm mammary 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 Sharpincpdm mice displayed reduced collagen arrangement and extracellular matrix (ECM) stiffness. Moreover, Sharpincpdm mammary 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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Gelatin solution, Type B, 2% in H2O, tissue culture grade, BioReagent, suitable for cell culture
Sigma-Aldrich
MISSION® esiRNA, targeting human SHARPIN
Sigma-Aldrich
2-Phenylindole, technical grade, 95%