BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms.
The adult, virgin mammary gland is a highly organized tree-like structure formed by ducts with hollowed lumen. Although lumen formation during pubertal development appears to involve apoptosis, the molecular mechanisms that regulate this process are not known. Here, we demonstrate that disruption of the BH3-only proapoptotic factor Bim in mice prevents induction of apoptosis in and clearing of the lumen in terminal end buds during puberty. However, cells that fill the presumptive luminal space are eventually cleared from the adjacent ducts by a caspase-independent death process. Within the filled Bim(-/-) ducts, epithelial cells are deprived of matrix attachment and undergo squamous differentiation prior to clearing. Similarly, we also detect squamous differentiation in vitro when immortalized mammary epithelial cells are detached from the matrix. These data provide important mechanistic information on the processes involved in sculpting the mammary gland and demonstrate that BIM is a critical regulator of apoptosis in vivo.
Mailleux
Arnaud A
AA
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Overholtzer
Michael
M
Schmelzle
Tobias
T
Bouillet
Philippe
P
Strasser
Andreas
A
Brugge
Joan S
JS
D000818:Animals; D023102:Anoikis; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000201:enzymology; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism*; D011627:Puberty / Q000502:physiology; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020169:Caspases