Trends in Cell Biology
Delivering the message: epimorphin and mammary epithelial morphogenesis☆
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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Cancer-driving mutations and variants of components of the membrane trafficking core machinery
2021, Life SciencesCitation Excerpt :A number of other SNAREs are known to be associated in various manners with cancer cells and tissues, although cancer-causing mutations and variants for these have not yet been reported. STX2/Epimorphin is a unique SNARE in that it also has a extracellular presence and function as a morphogen during development [293,294] Over-expression of STX2 in transgenic mouse promoted mammary adenocarcinoma [295], and in HCC cells enhanced their invasion and metastasis that involved an upregulation of matrix metalloproteinase-9 (MMP-9) via Focal adhesion kinase (FAK)/ERK signaling [296]. STX2 expression is also associated with colorectal cancer cell invasion, metastasis and poor patient prognosis via the activation of the nuclear factor κB (NF-κB) pathway, which could in turn transcriptionally enhanced STX2 expression [237,239].
Experimental mammary carcinogenesis - Rat models
2017, Life SciencesIdentification of ovarian gene expression patterns during vitellogenesis in Atlantic cod (Gadus morhua)
2012, General and Comparative EndocrinologyCitation Excerpt :For example, cyclin B was equally expressed between stages and is not translated until FOM to regulate many nuclear and cytoplasmic changes, including GVBD and spindle formation [54]. Similarly, syntaxin 2 (also known as epimorphin [60]) may not function until fertilization [12,29] or embryonic development [57]. These abundant stored messages in vitellogenic oocytes greatly impacted our ability to identify differential gene expression patterns, as intact mid and late vitellogenic tissues exhibited overall equal RNA content despite dramatic follicle size differences.
The impact of extracellular syntaxin4 on HaCaT keratinocyte behavior
2012, Biochemical and Biophysical Research CommunicationsEpimorphin-derived peptide antagonists remedy epidermal parakeratosis triggered by unsaturated fatty acid
2010, Journal of Dermatological ScienceCitation Excerpt :Interestingly, we found that an antagonistic peptide against epimorphin is capable of rescuing the oleic acid-triggered dyskeratosis and precocious development in keratinocytes. Epimorphin belongs to a member of t-SNARE protein family involved in intracellular membrane fusion events [17,24]. This begs the question, how does a protein with a role in intracellular vesicle fusion also regulate terminal differentiation in keratinocytes?
Mechanisms of Morphogenesis, Third Edition
2023, Mechanisms of Morphogenesis, Third Edition
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This article is the 12th review in our ‘Tube Morphogenesis’ series, which commenced in the August 2002 issue of TCB.