title: Lrig2-deficient mice are protected against PDGFB-induced glioma.
abstract: BACKGROUND
  The leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins constitute an integral membrane protein family that has three members: LRIG1, LRIG2, and LRIG3. LRIG1 negatively regulates growth factor signaling, but little is known regarding the functions of LRIG2 and LRIG3. In oligodendroglial brain tumors, high expression of LRIG2 correlates with poor patient survival. Lrig1 and Lrig3 knockout mice are viable, but there have been no reports on Lrig2-deficient mice to date.
  
  
  RESULTS
  Lrig2-deficient mice were generated by the ablation of Lrig2 exon 12 (Lrig2E12). The Lrig2E12-/- mice showed a transiently reduced growth rate and an increased spontaneous mortality rate; 20-25% of these mice died before 130 days of age, with the majority of the deaths occurring before 50 days. Ntv-a transgenic mice with different Lrig2 genotypes were transduced by intracranial injection with platelet-derived growth factor (PDGF) B-encoding replication-competent avian retrovirus (RCAS)-producing DF-1 cells. All injected Lrig2E12+/+ mice developed Lrig2 expressing oligodendroglial brain tumors of lower grade (82%) or glioblastoma-like tumors of higher grade (18%). Lrig2E12-/- mice, in contrast, only developed lower grade tumors (77%) or had no detectable tumors (23%). Lrig2E12-/- mouse embryonic fibroblasts (MEF) showed altered induction-kinetics of immediate-early genes Fos and Egr2 in response to PDGF-BB stimulation. However, Lrig2E12-/- MEFs showed no changes in Pdgfrα or Pdgfrβ levels or in levels of PDGF-BB-induced phosphorylation of Pdgfrα, Pdgfrβ, Akt, or extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). Overexpression of LRIG1, but not of LRIG2, downregulated PDGFRα levels in HEK-293T cells.
  
  
  CONCLUSIONS
  The phenotype of Lrig2E12-/- mice showed that Lrig2 was a promoter of PDGFB-induced glioma, and Lrig2 appeared to have important molecular and developmental functions that were distinct from those of Lrig1 and Lrig3.
authors.affiliation: Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Rondahl
authors.forename: Camilla
authors.initials: C
authors.lastname: Holmlund
authors.forename: Terese
authors.initials: T
authors.lastname: Karlsson
authors.forename: Baofeng
authors.initials: B
authors.lastname: Wang
authors.forename: Mahmood
authors.initials: M
authors.lastname: Faraz
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.forename: Håkan
authors.initials: H
authors.lastname: Hedman
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics; D002460:Cell Line; D004198:Disease Susceptibility; D005091:Exons / Q000235:genetics; D005260:Female; D017781:Genes, Immediate-Early / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016019:Survival Analysis; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: C587593:LRIG2 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D020797:Receptor, Platelet-Derived Growth Factor beta
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