Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Boston, MA, 02115, USA.
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2019 Jan 11;10(1):168. doi: 10.1038/s41467-018-08127-4.
In humans and in mice the formation of nephrons during embryonic development reaches completion near the end of gestation, after which no new nephrons are formed. The final nephron complement can vary 10-fold, with reduced nephron number predisposing individuals to hypertension, renal, and cardiovascular diseases in later life. While the heterochronic genes lin28 and let-7 are well-established regulators of developmental timing in invertebrates, their role in mammalian organogenesis is not fully understood. Here we report that the Lin28b/let-7 axis controls the duration of kidney development in mice. Suppression of let-7 miRNAs, directly or via the transient overexpression of LIN28B, can prolong nephrogenesis and enhance kidney function potentially via upregulation of the Igf2/H19 locus. In contrast, kidney-specific loss of Lin28b impairs renal development. Our study reveals mechanisms regulating persistence of nephrogenic mesenchyme and provides a rationale for therapies aimed at increasing nephron mass.
在人类和小鼠中，胚胎发育过程中肾单位的形成在妊娠末期接近完成，此后不再形成新的肾单位。终末肾单位的数量可变化 10 倍，肾单位数量减少使个体在以后的生活中易患高血压、肾脏和心血管疾病。虽然异时基因 lin28 和 let-7 是无脊椎动物发育时间的成熟调控因子，但它们在哺乳动物器官发生中的作用尚未完全了解。在这里，我们报告 Lin28b/let-7 轴控制小鼠肾脏发育的持续时间。直接或通过瞬时过表达 LIN28B 抑制 let-7 miRNAs 可以延长肾发生并增强肾功能，可能通过上调 Igf2/H19 基因座。相比之下，肾脏特异性缺失 Lin28b 会损害肾脏发育。我们的研究揭示了调节肾间充质持久性的机制，并为旨在增加肾单位数量的治疗提供了依据。
