PDF(Pubmed)
Abstract：
Fibroblast growth factors (Fgfs) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of Fgf8 in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the Fgf8 mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of Bak and Bax abrogates normal cell death and has minimal effect on renal development. However, in Fgf8 mutants, the combined loss of Bak and Bax rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in Fgf8 mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK/BAX and for subsequent steps involving, as yet, undefined roles in kidney development.
摘要：
成纤维细胞生长因子（Fgfs）长期以来一直参与对胚胎发育至关重要的过程。比如细胞存活，迁移,和差异化。器官发育的几种小鼠模型归因于FGF8的生存需求。这里,我们探讨了FGF8信号在肾脏发育中的潜在作用。我们先前已经证明，引起肾脏的中胚层祖细胞中Fgf8的条件性缺失会导致突变新生儿的肾脏发育不全。当在原始肾脏的皮质肾病区以及产生肾单位的肾囊泡中发生大量异常细胞死亡时，由FGF8丢失引起的有害后果开始在E14.5中显现出来。为了挽救Fgf8突变肾的细胞死亡,我们使编码促凋亡因子BAK和BAX的基因失活。在野生型背景下,Bak和Bax的丢失消除了正常的细胞死亡，对肾脏发育的影响很小。然而,在Fgf8突变体中，Bak和Bax的联合损失挽救了肾脏中的异常细胞死亡，并恢复了肾脏发育的某些措施：1）肾单位祖细胞数量大大增加；2）一些肾小球形式，在Fgf8突变体中很少观察到；3）在E18.5时，肾脏大小被挽救了约50％。功能性肾单位的发展，然而,没有获救。因此，FGF8信号传导是通过调节BAK/BAX和后续步骤所必需的，到目前为止，在肾脏发育中的作用不明确。
