Altered lymphopoiesis and immunodeficiency in miR-142 null mice.
MicroRNAs (miRNAs) are a class of powerful posttranscriptional regulators implicated in the control of diverse biological processes, including regulation of hematopoiesis and the immune response. To define the biological functions of miR-142, which is preferentially and abundantly expressed in immune cells, we created a mouse line with a targeted deletion of this gene. Our analysis of miR-142(-/-) mice revealed a critical role for this miRNA in the development and homeostasis of lymphocytes. Marginal zone B cells expand in the knockout spleen, whereas the number of T and B1 B cells in the periphery is reduced. Abnormal development of hematopoietic lineages in miR-142(-/-) animals is accompanied by a profound immunodeficiency, manifested by hypoimmunoglobulinemia and failure to mount a productive immune response to soluble antigens and virus. miR-142(-/-) B cells express elevated levels of B-cell-activating factor (BAFF) receptor (BAFF-R) and as a result proliferate more robustly in response to BAFF stimulation. Lowering the BAFF-R gene dose in miR-142(-/-) mice rescues the B-cell expansion defect, suggesting that BAFF-R is a bona fide miR-142 target through which it controls B-cell homeostasis. Collectively, our results uncover miR-142 as an essential regulator of lymphopoiesis, and suggest that lesions in this miRNA gene may lead to primary immunodeficiency.
Department of Molecular and Cellular Biology.
Nicholas J
NJ
Kramer
Department of Molecular and Cellular Biology.
Wei-Le
WL
Wang
Department of Molecular and Cellular Biology.
Estefany Y
EY
Reyes
Division of Hematopoietic Stem Cell and Leukemia Research.
Bijender
B
Kumar
Division of Hematopoietic Stem Cell and Leukemia Research.
Ching-Cheng
CC
Chen
Department of Virology, and.
Chandran
C
Ramakrishna
Department of Virology, and.
Edouard M
EM
Cantin
Division of Comparative Medicine, Beckman Research Institute, City of Hope, Duarte, CA; and.
Steven L
SL
Vonderfecht
Regulus Therapeutics, San Diego, CA.
Konstantin D
KD
Taganov
Regulus Therapeutics, San Diego, CA.
Nelson
N
Chau
Department of Molecular and Cellular Biology.
Mark P
http://orcid.org/0000-0003-4593-0669
MP
Boldin
D000818:Animals; D053265:B-Cell Activation Factor Receptor / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007153:Immunologic Deficiency Syndromes / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007160:Immunoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D038041:Lymphopoiesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology
D053265:B-Cell Activation Factor Receptor; D035683:MicroRNAs; C529102:Mirn142 microRNA, mouse; C486662:Tnfrsf13c protein, mouse