Dysregulated hematopoiesis and a progressive neurological disorder induced by expression of an activated form of the human common beta chain in transgenic mice.

Abstract

Previously we described activating mutations of h ␤ c , the common signaling subunit of the receptors for the hematopoietic and inflammatory cytokines, GM-CSF, IL-3, and IL-5. The activated mutant, h ␤ c FI ⌬ , is able to confer growth factor-independent proliferation on the murine myeloid cell line FDC-P1, and on primary committed myeloid progenitors. We have used this activating mutation to study the effects of chronic cytokine receptor stimulation. Transgenic mice were produced carrying the h ␤ c FI ⌬ cDNA linked to the constitutive promoter derived from the phosphoglycerate kinase gene, PGK-1 . Transgene expression was demonstrated in several tissues and functional activity of the mutant receptor was confirmed in hematopoietic tissues by the presence of granulocyte macrophage and macrophage colony-forming cells (CFU-GM and CFU-M) in the absence of added cytokines. All transgenic mice display a myeloproliferative disorder characterized by splenomegaly, erythrocytosis, and granulocytic and megakaryocytic hyperplasia. This disorder resembles the human disease polycythemia vera, suggesting that activating mutations in h ␤ c may play a role in the pathogenesis of this myeloproliferative disorder. In addition, these transgenic mice develop a sporadic, progressive neurological disease and display bilateral, symmetrical foci of necrosis in the white matter of brain stem associated with an accumulation of macrophages. Thus, chronic h ␤ c activation has the potential to contribute to pathological events in the central nervous system. ( J. Clin. Invest. 1998.

Association study of CSF2RB with schizophrenia in Irish family and case – control samples

“…1,28 In a mouse model, a mutant constitutively expressing CSF2RB develops sporadic and progressive neurologic disease and displays necrosis in the CNS. 29 In this study, we genotyped 10 SNPs (8 in intron, 2 in exon) in the CSF2RB gene in both the family and case -control samples. In the family sample, we found associations in SNPs rs11705394 and rs7285064.…”

“…It is critical for the activation of both the JAK/STAT (JAK2, STAT5) and MAP kinase pathways. 26,27 Using transgenic mice, D'Andrea et al 29 found that mutations in the CSF2RB gene may play a role in the pathogenesis of myeloproliferative disorders In addition, the transgenic mice developed a sporadic, progressive neurologic disorder and displayed bilateral, symmetrical foci of necrosis in the white matter of the brainstem associated with an accumulation of macrophages. 29 Thus, chronic CSF2RB activation has the potential to contribute to pathologic events in the CNS.…”

“…26,27 Using transgenic mice, D'Andrea et al 29 found that mutations in the CSF2RB gene may play a role in the pathogenesis of myeloproliferative disorders In addition, the transgenic mice developed a sporadic, progressive neurologic disorder and displayed bilateral, symmetrical foci of necrosis in the white matter of the brainstem associated with an accumulation of macrophages. 29 Thus, chronic CSF2RB activation has the potential to contribute to pathologic events in the CNS. Considering that both IL3 and IL3RA are reported to be associated with schizophrenia and that IL3 and IL3RA alone cannot form a functional receptor to transduce signal, CSF2RB becomes an attractive candidate gene for schizophrenia.…”

Identification of primary structural features that define the differential actions of IL-3 and GM-CSF receptors

“…Constitutively activated ␤ c can promote myeloproliferative disorders when expressed in marrow reconstitution systems or transgenic mice. 38,39 It is not clear, however, if activation of ␤ c alone is sufficient to promote myeloid cell development.…”

“…This perhaps reflects the myeloproliferative disorders observed in mice expressing constitutively activated mutant forms of h␤ c mutant. 38,39 A model for hGM R complex formation has been put forward based on results obtained with several different classes of activating h␤ c subunit mutations. 42 It is proposed that h␤ c complexes can exist in at least 2 active states, each of which can promote survival, proliferation, Data were obtained for the FDCP-mix cell cytokine receptor transfects cultured with either hIL-3 or hGM-CSF for 7 days.…”