BIM regulates apoptosis during mammary ductal morphogenesis, and its absence reveals alternative cell death mechanisms

Developmental Cell
Arnaud A MailleuxJoan S Brugge


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.


Feb 1, 1994·The Journal of Cell Biology·S M Frisch, H Francis
Aug 24, 1999·Circulation Research·A E LiT Finkel
Oct 20, 1999·Developmental Biology·T C KlinowskaCharles H Streuli
Aug 10, 2000·The American Journal of Pathology·L A O'ReillyAndreas Strasser
Jan 4, 2001·Cell·D C Huang, Andreas Strasser
Jan 5, 2002·Proceedings of the National Academy of Sciences of the United States of America·Keiko MiyoshiKhashayarsha Khazaie
Jan 11, 2002·Developmental Biology·Michael T LewisC W Daniel
Jan 10, 2003·The Journal of Investigative Dermatology. Symposium Proceedings·Richard L EckertFrederic Bone
Jun 12, 2003·Methods : a Companion to Methods in Enzymology·Jayanta DebnathJoan S Brugge
Jul 5, 2003·Nature Cell Biology·Mauricio J ReginatoJoan S Brugge
Feb 17, 2005·Nature Reviews. Molecular Cell Biology·Jerry E Chipuk, Douglas R Green
Apr 2, 2005·Nature Reviews. Molecular Cell Biology·Eleonora CandiGerry Melino
May 19, 2005·Molecular and Cellular Biology·Mauricio J ReginatoJoan S Brugge
Aug 3, 2005·The Journal of Clinical Investigation·Istvan BoldoghSanjiv Sur
Aug 9, 2006·Proceedings of the National Academy of Sciences of the United States of America·Michael OverholtzerDaniel A Haber


Jun 3, 2011·Archivum Immunologiae Et Therapiae Experimentalis·Toru Akiyama, Sakae Tanaka
May 3, 2011·Seminars in Immunopathology·Ian B Copland, Jacques Galipeau
May 13, 2010·Journal of Mammary Gland Biology and Neoplasia·Nathan J GoddePatrick O Humbert
Dec 20, 2008·Cell Death and Differentiation·Joanna F PearsonShona H Lang
Jan 1, 2010·Cell Death & Disease·B L Allen-PetersenM E Reyland
Dec 12, 2007·Cell Research·James A Keeble, Andrew P Gilmore
Oct 24, 2008·Nature Reviews. Molecular Cell Biology·David M Bryant, Keith Mostov
Jul 31, 2009·Oncogene·J D PiñonAndreas Villunger
Aug 17, 2010·Oncogene·Jayanta Debnath
Sep 24, 2010·Molecular Biology of the Cell·Kelly A WhelanMauricio J Reginato
Aug 13, 2010·Cold Spring Harbor Perspectives in Biology·John Muschler, Charles H Streuli
Aug 20, 2011·Genes & Development·Alexandra R GrassianJoan S Brugge
May 26, 2011·Science Signaling·Huei-Chi WenJ A Aguirre-Ghiso
Oct 21, 2009·Molecular and Cellular Biology·Anette HübnerRoger J Davis
May 12, 2010·Molecular and Cellular Biology·Xiaowen HeShaohua Li
Nov 28, 2007·Annual Review of Pathology·Christy HebnerJayanta Debnath
Jan 27, 2011·Cancer Research·Xiaoyan WangRosalie C Sears
Feb 18, 2011·Cancer Research·Ritwik GhoshCarlos L Arteaga
Dec 1, 2011·Cancer Research·Cristina CelluraleRoger J Davis
Jun 16, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Maria Soledad SosaJ A Aguirre-Ghiso
Oct 2, 2008·BMC Developmental Biology·Holly E BarkerJane E Visvader
May 22, 2009·Breast Cancer Research : BCR·Gray W Pearson, Tony Hunter
Jul 11, 2009·The AAPS Journal·Jayaraj RavindranBharat B Aggarwal
Jan 15, 2014·Oncogene·A Avivar-ValderasJ A Aguirre-Ghiso
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Tobias SchmelzleJoan S Brugge
May 18, 2013·ELife·Natalya N PavlovaStephen J Elledge
Sep 23, 2014·Cell Death and Differentiation·Lorenzo GalluzziGuido Kroemer
Nov 5, 2014·Nature Cell Biology·Ferenc A ScheerenMichael F Clarke
Jul 4, 2012·The Journal of Cell Biology·Yanmei QiShaohua Li
Mar 23, 2011·Annals of Medicine·Sara McNally, Finian Martin
Jul 17, 2015·Biotechnic & Histochemistry : Official Publication of the Biological Stain Commission·B Vesela, E Matalova
Sep 11, 2014·Journal of Cellular Physiology·Enrico GiarnieriGiuseppe Russo
Jan 31, 2015·Proceedings of the National Academy of Sciences of the United States of America·Alec E CerchiariZev J Gartner
Jul 3, 2009·Current Opinion in Cell Biology·Andrew P GilmoreJennefer Lindsay
Apr 23, 2009·The Journal of Steroid Biochemistry and Molecular Biology·Sarah J SantosSandra Z Haslam
Oct 28, 2008·Experimental Cell Research·Corinne GiustiPierre Golstein
Jun 6, 2015·Cell Death and Differentiation·F SchulerAndreas Villunger
Jul 18, 2009·EMBO Reports·Christina K McPheeMari Enoksson
Nov 7, 2008·Journal of Cellular Physiology·Shijie ShengArthur B Pardee
Sep 26, 2008·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Janice L WalkerMaria A Kukuruzinska
Jul 12, 2012·Anatomia, histologia, embryologia·M Colitti
Sep 8, 2011·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Chun-Chao WangKevin A Janes
Apr 21, 2011·Journal of Cellular Physiology·Ahmed RaafatRobert Callahan
Dec 1, 2009·Current Opinion in Cell Biology·Candia M KenificJayanta Debnath
Sep 12, 2015·Annual Review of Cell and Developmental Biology·Alex J BlaskyRytis Prekeris
Jul 20, 2010·The American Journal of Pathology·Craig HorbinskiNatasha Kyprianou
Apr 7, 2016·Cellular and Molecular Life Sciences : CMLS·Shefali Krishna, Michael Overholtzer
Apr 17, 2010·The American Journal of Pathology·Núria EritjaXavi Dolcet
Aug 28, 2014·Developmental Cell·Pavel I NedvetskySarah M Knox
Mar 4, 2011·Bioscience Reports·Carly Willenborg, Rytis Prekeris
Aug 10, 2013·Dose-response : a Publication of International Hormesis Society·Guanghu Wang
Oct 2, 2009·Organogenesis·Jonathan J Campbell, Christine J Watson
Feb 9, 2011·Current Biology : CB·Anirban DattaKeith Mostov
Feb 20, 2008·Current Opinion in Cell Biology·Fernando Martín-Belmonte, Keith Mostov
Mar 13, 2014·Seminars in Cell & Developmental Biology·Mirjam M Zegers
Apr 22, 2014·Seminars in Cell & Developmental Biology·Robert J Huebner, Andrew J Ewald
Oct 19, 2010·Biochimica Et Biophysica Acta·Rosario YerbesAbelardo López-Rivas
Sep 26, 2009·Developmental Biology·Deborah J Andrew, Andrew J Ewald
Jun 9, 2016·Archives of Oral Biology·T H N TeshimaS V Lourenço
Jun 30, 2016·Antioxidants & Redox Signaling·Marten Hornsveld, Tobias B Dansen
Feb 27, 2016·Cell Death and Differentiation·J A MasonZachary T Schafer
Apr 8, 2009·International Review of Cell and Molecular Biology·Fernando Martín-Belmonte, Alejo E Rodríguez-Fraticelli
Jul 28, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Christos VaklavasScott W Blume
Dec 3, 2015·Journal of Dental Research·T H N TeshimaA S Tucker
Mar 10, 2018·Biomedicines·Sergio RivasFrancisco Wandosell
May 15, 2016·Journal of Cell Science·Leena BakerSenthil K Muthuswamy
Dec 12, 2018·PloS One·Kylie L MillsHeather L Machado
Jan 25, 2018·Cell Death and Differentiation·Lorenzo GalluzziGuido Kroemer
Oct 1, 2016·Aging·Yulin LiDean W Felsher
Aug 8, 2014·Nature Reviews. Cancer·Cassandra L BuchheitZachary T Schafer
Mar 8, 2019·Frontiers in Oncology·Rose N NjorogeSarki A Abdulkadir
Aug 25, 2018·Journal of Cell Science·Clara R L OudenaardenPatrick W B Derksen
Mar 13, 2008·Médecine sciences : M/S·Arnaud A MailleuxJoan S Brugge
Feb 9, 2017·Journal of Mammary Gland Biology and Neoplasia·Ingrid S Paine, Michael T Lewis
Jun 16, 2016·The Journal of Biological Chemistry·Chunyue WengJohn E Shively
May 17, 2017·Cold Spring Harbor Perspectives in Biology·Heather C Bruner, Patrick W B Derksen
Oct 21, 2020·Cellular and Molecular Life Sciences : CMLS·Vincenzo SalemmePaola Defilippi
Jun 19, 2013·Cancer Research·Calli A DavisonZachary T Schafer
Mar 15, 2008·Cancer Research·Christopher G DanesDihua Yu
Nov 26, 2009·Molecular Cancer Therapeutics·Toru AkiyamaPeter F M Choong
Jan 10, 2020·Experimental and Molecular Pathology·Ellen Cristina Rivas LeonelSebastião Roberto Taboga
Nov 14, 2020·Genes & Development·Ayan T RayPhilippe Soriano
Jan 14, 2021·International Journal of Molecular Sciences·Han Yeoung LeeJong Kook Park
Feb 26, 2021·Nature Protocols·Caleb A DawsonJane E Visvader
Apr 10, 2021·Journal of Mammary Gland Biology and Neoplasia·Caleb A Dawson, Jane E Visvader
Oct 22, 2020·Seminars in Cell & Developmental Biology·Priscila Ferreira SlepickaCamila O Dos Santos

Related Concepts

Cell Differentiation Process
Embryonic Structures, Mammalian
Epithelial Cells
Cell Surface Proteins
Mice, Inbred C57BL
Proto-Oncogene Proteins
Apoptosis, Intrinsic Pathway

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