LIM Domain Binding Protein 1 (Ldb1) is Required for the Maintenance of Hematopoietic Stem Cells (81.4)

Abstract

Abstract Ldb1 is a ubiquitous nuclear protein that functions by interacting with and/or recruiting specific partners (including LMO2, SCL and GATA-1) to form multi-molecular DNA-binding transcription complexes. In the hematopoietic lineage, expression of Ldb1 is highest in lineage−Sca1+c-kit+ (LSK) multipotent progenitors. Ldb1 gradually decreases as cells mature within lymphoid or granulocyte/macrophage lineages, but remains high in erythroid lineage cells. We investigated the role of Ldb1 in hematopoiesis by conditional deletion of Ldb1 using a cre transgene driven by the Tie2 promotor; or by following the fate of Ldb1-null embryonic stem (ES) cells in mouse blastocyst chimeras. The number of Ter119+ (erythroid lineage) cells was decreased dramatically in Tie2Cre+Ldb1flox/flox mice, revealing a critical role for Ldb1 in erythropoiesis. Ldb1-null ES cells were capable of generating LSKs in the fetal liver and these cells could give rise to both myeloid and lymophoid lineage cells; however, the number of Ldb1−/− LSKs was markedly decreased at later stages of development. Following adoptive transfer, Ldb1-null fetal liver LSKs were rapidly lost indicating a failure of self-renewal or survival. Loss of Ldb1 was associated with an increase in multipotent progenitor (MPP) cells and a decrease in hematopoietic stem cells (HSCs), suggesting that Ldb1 participates in stem cell maintenance. These data provide the first evidence that LIM domain binding proteins function in hematopoiesis, and identify Ldb1 as a critical factor in regulating HSC maintenance/self-renewal.