The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis.
SED1, also known as MFG-E8, is a secreted protein composed of two EGF repeats (the second of which contains an RGD motif) and two discoidin/Factor V/VIII C domains. SED1 is expressed by a wide range of cell types, where it participates in diverse cellular interactions, such as sperm binding to the egg coat and macrophage recognition of apoptotic lymphocytes. Although SED1 was originally identified as a milk protein, its function in the mammary gland remains unclear; suggested functions include inhibition of viral infection and clearance of apoptotic cells during mammary gland involution. We report here that SED1 has an unexpected obligatory role during mammary gland development. Unlike that seen in WT glands, SED1-null glands show severely reduced branching from epithelial ducts and from terminal end buds, which are thin and poorly developed. SED1 is expressed by both luminal and myoepithelial cells in the developing epithelial duct, and binds to alpha(v) integrin receptors on myoepithelial cells leading to MAPK activation and cell proliferation. The absence of SED1 leads to greatly reduced levels of activated MAPK and a concomitant reduction in cell proliferation and branching throughout the epithelial tree. These results suggest that SED1 contributes, at least partly, to the intercellular signaling between luminal and myoepithelial cells that is required for branching morphogenesis.
Ensslin
Michael A
MA
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Shur
Barry D
BD
D020816:Amino Acid Motifs; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism*; D017209:Apoptosis; D002448:Cell Adhesion; D049109:Cell Proliferation; D000070821:Discoidins; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000737:chemistry*; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D004848:Epithelium / Q000378:metabolism; D005260:Female; D037102:Lectins / Q000737:chemistry*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008894:Milk Proteins / Q000737:chemistry* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry*; D020449:Repetitive Sequences, Amino Acid
D000954:Antigens, Surface; D000070821:Discoidins; D037102:Lectins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D015800:Protozoan Proteins; D004815:Epidermal Growth Factor; D020928:Mitogen-Activated Protein Kinases