Regulation of erythropoiesis by the neuronal transmembrane protein Lrfn2
Received 28 September 2006; received in revised form 26 January 2007; accepted 7 February 2007.
Objective
The transgenic mouse line MEnTCD2.5 expresses a dominant interfering Myb protein in a T-cell–specific fashion. When MEnTCD2.5 animals are crossed to a second line ubiquitously expressing Myc, they develop a rapid onset, fatal disease characterized by enlarged lymph nodes full of nonlymphoid cells. This study aimed to elucidate the reason for this anomalous non-T–cell phenotype.
Materials and Methods
We studied the cells by morphological analysis, surface marker staining, mRNA expression studies and in vitro colony-forming assays.
Results
Aberrant cells in MEnTCD2.5 lymph nodes are erythroblasts, and cooperation between MEnTCD2.5 and Myc causes severe erythroblastosis, but not erythroleukemia. MEnTCD2.5:Myc and MEnTCD2.5 animals have pronounced extramedullary erythropoiesis in their lymph nodes, and some increase in bone marrow–derived erythroid progenitors; no other MEnTCD2 transgenic line cooperates in this fashion with Myc, suggesting that the MEnTCD2.5 integration site, in intron 2 of the Lrfn2 gene, is of importance. To confirm this, in in vitro colony-forming assays, expression of wild-type Lrfn2 phenocopies the MEnTCD2.5 defect. Finally, Lrfn2 expression also causes the outgrowth of a bizarre cell type in colony-forming assays that stains positively for both early hematopoietic and fibroblast/fibrocyte surface markers.
Conclusions
The Lrfn2 protein, a transmembrane adhesion-type molecule, is able to subvert hematopoietic differentiation to increase erythropoiesis. In cooperation with Myc, this leads to erythroblastosis. Lrfn2 may also be involved in colony forming units-fibroblast regulation. As Lrfn2 expression is detectable in wild-type bone marrow, it likely plays a novel role during normal hematopoiesis.
aInstitute of Cancer Research, CR-UK Centre for Cell and Molecular Biology, London, UK
bInstitute of Biomedical Research, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK
Offprint requests to: Kathleen Weston, Ph.D., Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK
∗ Dr. Castellanos current address: Department de Genètica i de Microbiologia, Fac. Ciencies, Campus Bellaterra, Edifici C, Universitat Autònoma de Barcelona, Barcelona 08030, Spain.
ABSTRACT