Multiple Apoptotic Defects In Hematopoietic Cellsfrom Mice Lacking Lipocalin 24p3.

Abstract 1560

The lipocalin mouse 24p3 has been implicated in diverse physiological processes including apoptosis, iron trafficking, development and innate immunity. Studies from our lab as well as others demonstrated the pro-apoptotic activity of 24p3 in a variety of cultured models. However, a general role for the lipocalin 24p3 in the homeostasis of the hematopoietic system has not been tested in vivo. To study the role of 24p3 in apoptosis, we derived 24p3 null mice on 129 SVE and C57BL/6 genetic backgrounds, which enabled us to test, for the first time, the in vivo role of 24p3 without any confounders. We find that homozygous 24p3-/- mice have apoptotic defects in several hematopoietic lineages, including neutrophils, cytokine-dependent mast cells, thymocytes and erythroid cells. The progressive accumulation of lymphoid, myeloid and erythroid cells in 24p3-/- mice demonstrate the importance of 24p3 in the regulation of homeostasis of hematopoietic cells in adults. Thymocytes isolated from 24p3 null mice displayed resistance to apoptosis-induced by Dexamethasone. In addition, Dexamethasone-induced apoptosis is also reduced in 24p3-/- mice. Collectively, these results indicate that 24p3 is an important target gene involved in GC-mediated apoptosis of lymphocytes and other hematopoietic cell types. Finally, our results also indicate that the genetic background of mice can modulate the effects of 24p3 deficiency. In summary, the results presented here, in conjunction with those of previous studies, reveal 24p3 as a regulator of the hematopoietic compartment with important roles in normal physiology and disease progression.