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.

成纤维细胞生长因子 ( Fgfs ) 长期以来一直与胚胎发育的关键过程有关，例如细胞存活、迁移和分化。几种器官发育的小鼠模型将促生存要求特别归因于 FGF8。在这里，我们探讨了促存活 FGF8 信号在肾脏发育中的潜在作用。我们之前已经证明，在产生肾脏的中胚层祖细胞中条件性删除Fgf8会导致突变新生儿的肾发育不全。由 FGF8 丢失引起的有害后果在 E14.5 时开始显现，当时在未发育肾脏的皮质肾发生区以及产生肾元的肾囊泡中发生大量异常细胞死亡。为了挽救细胞死亡Fgf8突变体肾脏，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的缺失会消除正常的细胞死亡，并且对肾脏发育的影响很小。然而，在Fgf8突变体中， Bak和Bax的联合缺失挽救了肾脏中的异常细胞死亡并恢复了肾脏发育的一些措施：1）肾单位祖细胞数量大大增加；2) 一些肾小球形式，在Fgf8中很少观察到变种人；和 3) 在 E18.5 时，肾脏大小减少了约 50%。然而，功能性肾单位的发育并没有得到挽救。因此，FGF8 信号是通过调节 BAK/BAX 和涉及肾脏发育中尚未定义的作用的后续步骤的肾单位祖细胞存活所必需的。