Trends in Cell Biology
Volume 13, Issue 8, August 2003, Pages 426-434
Journal home page for Trends in Cell Biology

Delivering the message: epimorphin and mammary epithelial morphogenesis

https://doi.org/10.1016/S0962-8924(03)00146-6Get rights and content

Abstract

The mammary gland consists of a highly branched tubular epithelium surrounded by a complex mesenchymal stroma. Epimorphin is an extracellular protein that is expressed by mammary mesenchymal cells that directs epithelial morphogenesis. Depending upon the context of presentation – polar versus apolar – epimorphin can selectively direct two key processes of tubulogenesis: branching morphogenesis (processes involved in tubule initiation and extension) and luminal morphogenesis (required for enlargement of tubule caliber). Here, we outline the fundamentals of mammary gland development and describe the function of epimorphin in these processes. We conclude with a review of recent studies that suggest similar morphogenic roles for epimorphin in other glandular organs.

Section snippets

The double-layered tube: structural organization and developmental morphogenesis of the mammary gland

The branching ducts and terminal alveoli in the mammary gland are largely elaborated from a double-layered epithelial tube (Fig. 2). The inner layer is composed of luminal epithelial cells, bound into a continuous surface by a combination of tight junctions, desmosomes and E-cadherin-mediated adherens junctions. The outer layer is composed of myoepithelial cells, which play an essential role in glandular morphogenesis and are required for expelling milk during lactation. The double-layered

Context matters: epimorphin as a multifunctional morphogen

The role of epimorphin as an extracellular morphogen was originally identified in studies of lung branching morphogenesis 28, 29. The same molecule was subsequently identified as syntaxin-2, a member of the syntaxin family of vesicle fusion proteins 30, 31 [epimorphin/syntaxin-2 appears to be unique in this regard because, so far, no other syntaxin family member is known to share this dual topology (see Box 1 for additional details on the relationship between epimorphin and syntaxins)]. Lung

Showing the way: downstream effects of epimorphin

Epimorphin signaling has been implicated in two mechanisms that are crucial for mammary gland development. First, epimorphin has been shown to stimulate the expression of the transcription factor CCAAT/enhancer binding protein-β (C/EBPβ) [13], which is essential for proper mammary morphogenesis and for mammary epithelial cell fate determination [34]. Epimorphin treatment increases the ratio of the shorter isoform of C/EBPβ (LIP) relative to the longer isoform (LAP) both in culture and in the

Branching out: epimorphin and the morphogenesis of glandular organs

Epimorphin localization has been studied in several different tissues (Table 1) and distinct morphogenic effects have been found in many of these. In addition to its effects on mammary epithelial cells, epimorphin has been found to stimulate luminal morphogenesis of primary gall-bladder [37], pancreas [38] and liver 39, 40 epithelial cells. In liver, it also induces functional differentiation [39]. Epimorphin also stimulates branching morphogenesis of lung organoids 28, 41 and cultured

Concluding remarks

Given that postpubertal mammary gland development is regulated by systemic hormones, one of the most immediate questions is how epimorphin action is coordinated with, or controlled by, hormone signaling. The overlapping roles of the different hormones complicate such investigations; as a starting point, it might be most productive to focus on hormonal signals known to stimulate side-branching, the activity for which epimorphin has been best characterized. In this regard, it is notable that both

Acknowledgements

Our work was supported by the US Department of Energy, Office of Biological and Environmental Research (contract DE-AC03–76SF00098) and a National Institutes of Health (grant CA57621), as well as an ‘Innovator’ grant from the US Army to M.J.B. (DAMD17-02-1-0438), an American Cancer Society fellowship to D.R., and support from the Science and Technology Agency of Japan to Y.H. We thank C. Nelson, J. Bascom, H. Liu, P. Kenny and V. Novaro for insightful discussions and editorial comments.

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