| First Author | Houston IB | Year | 2007 |
| Journal | Exp Hematol | Volume | 35 |
| Issue | 7 | Pages | 1056-68 |
| PubMed ID | 17588474 | Mgi Jnum | J:123079 |
| Mgi Id | MGI:3717036 | Doi | 10.1016/j.exphem.2007.04.005 |
| Citation | Houston IB, et al. (2007) Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality. Exp Hematol 35(7):1056-68 |
| abstractText | OBJECTIVE: It has been demonstrated that high concentration of the transcription factor PU.1 (encoded by Sfpi1) promotes macrophage development, whereas low concentration induces B-cell development in vitro. This has led to the hypothesis that lower levels of PU.1 activity are required for B cell than for macrophage development in vivo. We utilized an allele of Sfpi1 (termed BN) with a mutation in the first coding exon, which resulted in a reduction of PU.1 expression in order to test this hypothesis. MATERIALS AND METHODS: Using gene targeting in embryonic stem cells, two ATG-start site codons of PU.1 were mutated, resulting in reduced PU.1 expression originating from a third start codon. Mice were assayed for phenotypic abnormalities using fluorescence-activated cell sorting, microscopy, and colony-forming ability. In addition, isolated cells were tested for their differentiation potential in vitro and in vivo. RESULTS: Lymphoid and myeloid cells derived from cultured Sfpi1(BN/BN) fetal liver cells had reduced levels of PU.1 expression and activity. B-cell development was intrinsically blocked in cells isolated from Sfpi1(BN/BN) mice. In addition, myeloid development was impaired in Sfpi1(BN/BN) fetal liver. However, neonatal Sfpi1(BN/BN) mice had a dramatic expansion and infiltration of immature myeloid cells. CONCLUSION: Contrary to our original hypothesis, high levels of PU.1 activity are required to induce both myeloid and B-cell development. In addition, neonatal mice homozygous for the hypomorphic allele acquire a myeloproliferative disorder and die within 1 month of age. |
