title: miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.
abstract: B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Maryaline
authors.initials: M
authors.lastname: Coffre
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Benhamou
authors.affiliation: Harvard Medical School, Pathology, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rieß
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Blumenberg
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Snetkova
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Hines
authors.affiliation: Harvard Medical School, Pathology, Boston, MA 02115, USA.
authors.forename: Tirtha
authors.initials: T
authors.lastname: Chakraborty
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Sofia
authors.initials: S
authors.lastname: Bajwa
authors.affiliation: Harvard Medical School, Pathology, Boston, MA 02115, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Skirball Institute, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Mark M W
authors.initials: MMW
authors.lastname: Chong
authors.affiliation: Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Lelise
authors.initials: L
authors.lastname: Getu
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA; Department of Medicine, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Gregg J
authors.initials: GJ
authors.lastname: Silverman
authors.affiliation: Department of Urology, UCSF, San Francisco, CA 94143, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Blelloch
authors.affiliation: Skirball Institute, NYU School of Medicine, New York, NY 10016, USA; The HHMI, NYU School of Medicine, New York, NY 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Harvard Medical School, Pathology, Boston, MA 02115, USA.
authors.forename: Dinis
authors.initials: D
authors.lastname: Calado
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion, Haifa 31096, Israel.
authors.forename: Doron
authors.initials: D
authors.lastname: Melamed
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Skok
authors.affiliation: Harvard Medical School, Pathology, Boston, MA 02115, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: sergei.koralov@nyumc.org.
authors.forename: Sergei B
authors.initials: SB
authors.lastname: Koralov
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics*; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007147:Immunoglobulin Light Chains / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017393:RNA Editing / Q000235:genetics*; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D019076:Transgenes
chemical_list: C474044:Dgcr8 protein, mouse; D051858:Forkhead Transcription Factors; D007147:Immunoglobulin Light Chains; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C513400:Drosha protein, mouse; D043244:Ribonuclease III
keywords: B cell development; B lymphocytes; DGCR8; Dicer; Drosha; PI3K/AKT; PTEN; RAG; miRNA; receptor editing