Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Nat Commun. 2013;4:1398. doi: 10.1038/ncomms2408.
Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period.
大多数肾单位成分，包括肾小球和肾小管，都来源于后肾间充质。整体分化为每个成分在出生时完成，但连接围产期和成人肾脏的分子事件仍然难以捉摸。Dullard 从非洲爪蟾肾脏中克隆出来，编码一种负调控 BMP 信号的磷酸酶。在这里，我们报道 Dullard 在小鼠后肾间充质中的缺失导致出生后肾单位维持失败，导致成年前死亡。出生后 3 周内，大量细胞凋亡导致肾单位成分丢失，形成一个具有薄皮层和髓质的大空腔。突变体肾单位中磷酸化的 Smad1/5/8 上调，可能是通过 Dullard 对 BMP 信号的细胞自主抑制作用。重要的是，BMP 受体激酶抑制剂 LDN-193189 的给药部分挽救了 Dullard 缺失引起的缺陷。因此，Dullard 将 BMP 信号维持在适当的水平，这是出生后肾单位维持所必需的。
