Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo.
Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells. Here we report the generation of ELMO1-deficient mice, which we found to be unexpectedly viable and grossly normal. However, they had a striking testicular pathology, with disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells and decreased sperm output. Subsequent in vitro and in vivo analyses revealed a crucial role for ELMO1 in the phagocytic clearance of apoptotic germ cells by Sertoli cells lining the seminiferous epithelium. The engulfment receptor BAI1 and RAC1 (upstream and downstream of ELMO1, respectively) were also important for Sertoli-cell-mediated engulfment. Collectively, these findings uncover a selective requirement for ELMO1 in Sertoli-cell-mediated removal of apoptotic germ cells and make a compelling case for a relationship between engulfment and tissue homeostasis in vivo.
Elliott
Michael R
MR
Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.
Zheng
Shuqiu
S
Park
Daeho
D
Woodson
Robin I
RI
Reardon
Michael A
MA
Juncadella
Ignacio J
IJ
Kinchen
Jason M
JM
Zhang
Jun
J
Lysiak
Jeffrey J
JJ
Ravichandran
Kodi S
KS
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D006706:Homeostasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D012670:Seminiferous Epithelium / Q000166:cytology / Q000473:pathology; D012708:Sertoli Cells / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013094:Spermatozoa / Q000166:cytology* / Q000473:pathology; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
D048868:Adaptor Proteins, Signal Transducing; C524949:Adgrb1 protein, mouse; D042501:Angiogenic Proteins; C510359:ELMO1 protein, mouse; D009479:Neuropeptides; D010718:Phosphatidylserines; C484602:Rac1 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein