title: The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils.
abstract: The lamin B receptor (LBR) is an integral nuclear envelope protein that interacts with chromatin and has homology to sterol reductases. Mutations in LBR result in Pelger-Huët anomaly and HEM-Greenberg skeletal dysplasia, whereas in mice Lbr mutations result in ichthyosis. To further understand the function of the LBR and its role in disease, we derived a novel mouse model with a gene-trap insertion into the Lbr locus (Lbr(GT/GT)). Phenotypically, the Lbr(GT/GT) mice are similar to ichthyosis mice. The Lbr(GT/GT) granulocytes lack a mature segmented nucleus and have a block in late maturation. Despite these changes in nuclear morphology, the innate granulocyte immune function in the killing of Staphylococcus aureus bacteria appears to be intact. Granulocyte differentiation requires the transcription factor C/EBPepsilon. We identified C/EBPepsilon binding sites within the Lbr promoter and used EMSAs and luciferase assays to show that Lbr is transcriptionally regulated by C/EBPepsilon. Our findings indicate that the Lbr(GT/GT) mice are a model for Pelger-Huët anomaly and that Lbr, under transcriptional regulation of C/EBPepsilon, is necessary for morphological but not necessarily functional granulocyte maturation.
authors.affiliation: Cancer and Developmental Biology Laboratory, CCR, Frederick, MD 21702, USA.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Cohen
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Klarmann
authors.forename: Krisada
authors.initials: K
authors.lastname: Sakchaisri
authors.forename: Jason P
authors.initials: JP
authors.lastname: Cooper
authors.forename: Douglas
authors.initials: D
authors.lastname: Kuhns
authors.forename: Miriam
authors.initials: M
authors.lastname: Anver
authors.forename: Peter F
authors.initials: PF
authors.lastname: Johnson
authors.forename: Simon C
authors.initials: SC
authors.lastname: Williams
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D053144:Cell Nucleus Shape; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D018375:Neutrophil Activation; D009504:Neutrophils / Q000166:cytology* / Q000502:physiology; D010381:Pelger-Huet Anomaly / Q000196:embryology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000502:physiology; D014158:Transcription, Genetic; D000097682:Lamin B Receptor
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C489468:Cebpe protein, mouse