Laminin alpha 5 regulates mammary gland remodeling through luminal cell differentiation and Wnt4-mediated epithelial crosstalk.

Johanna I Englund,Julia Döhla,Nalle Pentinmikko,Sharif Iqbal,Manuel Patarroyo,Hanne Cojoc,Pekka Katajisto,Leander Blaas,Alexandra Ritchie

doi:10.1242/dev.199281

Johanna I Englund, Julia Döhla + Show 7 more

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https://doi.org/10.1242/dev.199281

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Abstract

ABSTRACTEpithelial attachment to the basement membrane (BM) is essential for mammary gland development, yet the exact roles of specific BM components remain unclear. Here, we show that Laminin α5 (Lama5) expression specifically in the luminal epithelial cells is necessary for normal mammary gland growth during puberty, and for alveologenesis during pregnancy. Lama5 loss in the keratin 8-expressing cells results in reduced frequency and differentiation of hormone receptor expressing (HR+) luminal cells. Consequently, Wnt4-mediated crosstalk between HR+ luminal cells and basal epithelial cells is compromised during gland remodeling, and results in defective epithelial growth. The effects of Lama5 deletion on gland growth and branching can be rescued by Wnt4 supplementation in the in vitro model of branching morphogenesis. Our results reveal a surprising role for BM-protein expression in the luminal mammary epithelial cells, and highlight the function of Lama5 in mammary gland remodeling and luminal differentiation.

Highlights

Postnatal development of the mammary gland occurs by branching and elongation during puberty, and by extensive remodeling during pregnancy (Macias and Hinck, 2012; Paine and Lewis, 2017)
Differential expression of laminin isoforms in distinct cell types of the mammary epithelium To explore the role of specific laminins in the mammary gland, we first studied their expression during the pubertal gland expansion, which is marked by terminal end bud (TEB) structures (Macias and Hinck, 2012)
Using in situ hybridization (ISH) to detect the expression of Lama1, 3, 4 and 5, we observed that both Lama1 and 3 were expressed by the basal cells of growing TEBs (Fig. 1A) and established ducts (Fig. S1A)

Summary

Introduction

Postnatal development of the mammary gland occurs by branching and elongation during puberty, and by extensive remodeling during pregnancy (Macias and Hinck, 2012; Paine and Lewis, 2017). The mammary microenvironment contributes to various properties of mammary epithelial cells (MECs), including proliferation, survival and differentiation (Inman et al, 2015). Handling Editor: Liz Robertson Received 10 December 2020; Accepted 10 May 2021 the specialized layer of the extracellular matrix (ECM) called the basement membrane (BM) is crucial for cultured mammary epithelial cells and for mammary gland morphogenesis in vivo (Inman et al, 2015; Weaver et al, 1997; LaBarge et al, 2009). The BM acts as a physical barrier separating the epithelium from the stroma and as a scaffold supporting epithelial adhesion and tissue architecture (Yurchenco, 2011). The BM regulates tissue homeostasis by supplying cells with growth factors and other signaling molecules, and by regulating their availability to the cells (Yurchenco, 2011)

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