Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development.
Notch signaling regulates lineage decisions at multiple stages of lymphocyte development, and Notch activation requires the endocytosis of Notch ligands in the signal-sending cells. Four E3 ubiquitin ligases, Mind bomb (Mib) 1, Mib2, Neuralized (Neur) 1, and Neur2, regulate the Notch ligands to activate Notch signaling, but their roles in lymphocyte development have not been defined. We show that Mib1 regulates T and marginal zone B (MZB) cell development in the lymphopoietic niches. Inactivation of the Mib1 gene, but not the other E3 ligases, Mib2, Neur1, and Neur2, abrogated T and MZB cell development. Reciprocal bone marrow (BM) transplantation experiments revealed that Mib1 in the thymic and splenic niches is essential for T and MZB cell development. Interestingly, when BM cells from transgenic Notch reporter mice were transplanted into Mib1-null mice, the Notch signaling was abolished in the double-negative thymocytes. In addition, the endocytosis of Dll1 was impaired in the Mib1-null microenvironment. Moreover, the block in T cell development and the failure of Dll1 endocytosis were also observed in coculture system by Mib1 knockdown. Our study reveals that Mib1 is the essential E3 ligase in T and MZB cell development, through the regulation of Notch ligands in the thymic and splenic microenvironments.
Song
Ran
R
Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea.
Kim
Young-Woong
YW
Koo
Bon-Kyoung
BK
Jeong
Hyun-Woo
HW
Yoon
Mi-Jeong
MJ
Yoon
Ki-Jun
KJ
Jun
Dong-Jae
DJ
Im
Sun-Kyoung
SK
Shin
Juhee
J
Kong
Myoung-Phil
MP
Kim
Kyong-Tai
KT
Yoon
Keejung
K
Kong
Young-Yun
YY
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D004705:Endocytosis; D005434:Flow Cytometry; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D034622:RNA Interference; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology* / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; C470629:MIB1 protein, mouse; D044767:Ubiquitin-Protein Ligases