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Insights Into the Role of Connexins in Mammary Gland Morphogenesis and Function

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Insights Into the Role of Connexins in Mammary Gland Morphogenesis and Function REPRODUCTIONREVIEW Insights into the role of connexins in mammary gland morphogenesis and function Michael K G Stewart1, Jamie Simek1 and Dale W Laird1,2 Departments of 1Physiology and Pharmacology and 2Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada N6A 5C1 Correspondence should be addressed to D W Laird; Email: [email protected] Abstract Gap junctions formed of connexin subunits link adjacent cells by direct intercellular communication that is essential for normal tissue homeostasis in the mammary gland. The mammary gland undergoes immense remodeling and requires exquisite regulation to control the proliferative, differentiating, and cell death mechanisms regulating gland development and function. The generation of novel genetically modified mice with reduced or ablated connexin function within the mammary gland has advanced our understanding of the role of gap junctions during the complex and dynamic process of mammary gland development. These studies have revealed an important stage- specific role for Cx26 (GJA1) and Cx43 (GJB2), while Cx30 (GJB6) and Cx32 (Gjb1) can be eliminated without compromising the gland. Yet, there remain gaps in our understanding of the role of mammary gland gap junctions. Reproduction (2015) 149 R279–R290 Introduction environment or through poorly understood regulatory protein–protein interactions (Goodenough & Paul 2003, Gap junctions are formed when six connexins co- Laird 2010). Importantly, gap junctions are expressed in oligomerize to form a connexon, or hemichannel, almost every cell type in the human body, including those which docks with a connexon from an adjacent cell to of the breast, and are dynamically regulated throughout form a gap junction channel (Laird 2006). Gap junction organ and tissue morphogenesis, suggesting a role in the channels directly link the cytoplasm of adjacent cells regulation of developmental processes (Wei et al. 2004, allowing for the exchange of molecules !1 kDa in size 2C Laird 2006). As the majority of its development occurs that includes ions and second messengers (Ca ,IP3, after birth, the breast remains a fascinating organ to study cAMP) in a process known as gap junctional intercellular the role of connexins in development. communication (GJIC) (Laird 2006). We now know that The human breast, similar to that of the mouse 21 connexins exist in humans, while 20 connexins are mammary gland, functions to provide both nutrition found in mouse, and generally multiple connexins and passive immunological protection against pathogens are expressed within the same cell (Laird 2006). during nursing. Both are composed of a bilayered However, channels formed by one connexin cannot epithelial network consisting of a single luminal layer always compensate for the loss of channel function from surrounded by a layer of myoepithelial cells separated another because various connexins possess distinct from the mammary stroma by a basement membrane gating properties and conductance when forming (Richert et al. 2000, Geddes 2007). However, while the homomeric connexons formed exclusively of one non-pregnant rodent mammary gland consists entirely of connexin isoform (Laird 2006, Harris 2007). In addition, a single ductal tree consisting of blunt ended ducts that some connexins, such as Cx26 (Gjb2), Cx30 (Gjb6), and develop alveolar buds in response to the estrous cycle Cx32 (Gjb1), are able to intermix and form heteromeric within a mainly adipose-rich mammary fat pad, the connexons composed of multiple connexin isoforms, human mammary gland contains 15–20 independent which display altered permeability characteristics and branching epithelial networks that begin as terminal duct gating sensitivities that likely reflect the biological need lobular units composed of alveoli and ducts surrounded of the cell type in vivo (Harris 2007, Locke et al. 2007). by fibrous connective tissue (Sternlicht et al. 2006, In addition, apart from GJIC-dependent functions, Geddes 2007). Importantly, both human and mouse connexins may also control cellular function indepen- mammary glands undergo extensive proliferation and dent of GJIC through the formation of gap junction secretory differentiation of epithelium as the breast hemichannels linking the intracellular and extracellular develops into a secretory gland during lactation, which q 2015 Society for Reproduction and Fertility DOI: 10.1530/REP-14-0661 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/01/2021 10:41:16AM via free access R280 M K G Stewart and others require tight regulation of hormonal and growth factor morphogenic changes in the pregnant mammary gland, cues as well as epithelial–epithelial and epithelial– luminal epithelial cells undergo differentiation as many stromal interactions, and direct cell–cell communication genes involved in milk synthesis begin to be expressed through gap junctions (Hennighausen & Robinson 2005, during midpregnancy (Anderson et al. 2007). With the Geddes 2007, McLachlan et al. 2007, Macias & Hinck withdrawal of progesterone at parturition, the gland 2012). Therefore, it is unsurprising that the human and undergoes secretory activation as the mammary gland is mouse epithelial stem cell hierarchies share many set up as an exocrine gland to perform its main function parallels as reviewed by Visvader (2009). Ultimately, to produce, secrete, and deliver milk (Pang & Hartmann due to these similarities between the mouse and human 2007). The gland functions to produce milk until mammary gland, the mouse mammary gland has weaning of the pups where the buildup of milk within become a useful model to further our understanding of alveoli acts as a trigger for the mammary gland to the mechanisms associated with gland development and undergo involution. This two-step process is charac- disease, particularly through our ability to genetically terized by extensive cell death and remodeling that manipulate molecular functions by mutation or ablation returns the mammary gland back to the adult gland state (Howlin et al. 2006, Brisken 2013). The evaluation of (Watson & Kreuzaler 2011). The first phase of involution genetically modified mice has extended our under- is characterized by extensive cell death, triggered by standing of the role of connexins in the mammary gland, the activation of the LIF/Stat3 pathway, while the second which is discussed in this review. phase of involution is characterized by remodeling of the extracellular matrix, adipocyte differentiation, and alveolar collapse (Macias & Hinck 2012). Mouse mammary gland development The development of the murine mammary gland begins with the development of the milk lines at embryonic day Expression of connexins in the 10 (Cowin & Wysolmerski 2010). By embryonic day 11.5, rodent mammary gland the milk lines develop into five pairs of mammary gland placodes which progress into mammary gland buds and Up until about 2004, the majority of studies evaluating ultimately a rudimentary ductal structure (Macias & connexins in the rodent mammary gland focused on Hinck 2012). Following birth, this rudimentary structure characterizing connexin expression, localization, and develops isometrically with body weight until the onset of regulation (Fig. 1). Gap junctions were first detected joining puberty (Howlin et al. 2006). The hormonal secretion of ductal epithelial cells in 3 to 9-week old mammary glands estrogen and growth hormone (GH) then drives the first of mice (Pitelka et al. 1973). These likely represented gap main phase of development by orchestrating ductal junctions made from Cx43 (Gja1) as the vast majority of elongation from proliferative structures known as studies agree that Cx43 is expressed in the basal epithelium terminal end buds that invade the surrounding stroma and stroma, and further represents the major connexin and bifurcate creating new primary branches. These expressed in the non-pregnant rodent mammary gland branches together with secondary lateral side branching (Pozzi et al. 1995, Locke et al.2004, Talhouk et al. 2005, loosely fill the mammary gland fat pad (Macias & Hinck Lambe et al.2006, Plante & Laird 2008). Cx43 is also 2012). The adult mammary gland continues to undergo reported to be transcriptionally upregulated in 5 to 6-week additional tertiary branching in response to cyclical old virgin mice, suggesting a role in the development of ovarian estrus cycles further developing a highly pubertal mammary gland (Lambe et al.2006). Other branched epithelial network with the development of connexins expressed between luminal cells of the non- alveolar-like structures that cyclically regress until the pregnant mammary gland are Cx26, Cx32,andCx30 onset of pregnancy (Sternlicht et al. 2006). (Talhouk et al. 2005, Plante & Laird 2008). However, these The second phase of mammary gland development connexins remain poorly characterized based on low occurs following the onset of pregnancy and is connexin expression, poor sensitivity of anti-connexin characterized by massive amounts of cell proliferation antibodies, variations in tissue processing, and differences and tissue remodeling (Hennighausen & Robinson in mouse strains being investigated (Monaghan et al. 1994, 2005). The gland undergoes extensive alveolar develop- Locke et al. 2000, 2004, Yamanak a et al. 2001). ment to acquire a secretory lobuloalveolar phenotype Following the onset of pregnancy, the connexin (Oakes et al. 2006). During early pregnancy, prolactin expression
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