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Human Molecular Genetics Advance Access published online on July 11, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn191
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Published by Oxford University Press 2008

The Lamin B Receptor under transcriptional control of C/EBP{varepsilon} is required for morphological but not functional maturation of neutrophils

Tatiana V. Cohen1, Kimberly D. Klarmann1,2, Krisada Sakchaisri3, Jason P. Cooper4, Douglas Kuhns5, Miriam Anver6, Peter F. Johnson3, Simon C. Williams4, Jonathan R. Keller1,2 and Colin L. Stewart1,*,{dagger}

1 Cancer and Developmental Biology Laboratory, CCR, National Cancer Institute, Frederick, MD 21702 2 Basic Research Program, Laboratory of Cancer Prevention, SAIC-Frederick, Inc., NCI Frederick, Frederick, Maryland 21702 3 Laboratory of Protein Dynamics and Signaling, CCR, National Cancer Institute, Frederick, MD 21702 4 Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA 5 Clinical Services Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD, 21702, USA 6 Laboratory Animal Sciences Program, Pathology/Histotechnology Laboratory, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702

* Corresponding Author: Tel: +6564070156. Fax: +6564642049 E-mail: colin.stewart{at}imb.a-star.edu.sg

Received May 6, 2008; Revised July 3, 2008; Accepted July 3, 2008

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 genetrap insertion into the Lbr locus (LbrGT/GT). Phenotypically, the LbrGT/GT mice are similar to ichthyosis mice. The LbrGT/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 S. aureus bacteria appears to be intact. Granulocyte differentiation requires the transcription factor C/EBP{varepsilon}. We identified C/EBP{varepsilon} binding sites within the Lbr promoter and used EMSAs and luciferase assays to show that Lbr is transcriptionally regulated by C/EBP{varepsilon}. Our findings indicate that the LbrGT/GT mice are a model for Pelger-Huët anomaly and that Lbr, under transcriptional regulation of C/EBP{varepsilon}, is necessary for morphological but not necessarily functional granulocyte maturation.

{dagger} Present address: Institute of Medical Biology, 8A Biomedical Grove, Immunos, Singapore 138668


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