FAT4 通过调节 RET 信号来精细调控肾脏发育。
FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling.
机构信息
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
出版信息
Dev Cell. 2019 Mar 25;48(6):780-792.e4. doi: 10.1016/j.devcel.2019.02.004. Epub 2019 Mar 7.
FAT4 mutations lead to several human diseases that disrupt the normal development of the kidney. However, the underlying mechanism remains elusive. In studying the duplex kidney phenotypes observed upon deletion of Fat4 in mice, we have uncovered an interaction between the atypical cadherin FAT4 and RET, a tyrosine kinase receptor essential for kidney development. Analysis of kidney development in Fat4 kidneys revealed abnormal ureteric budding and excessive RET signaling. Removal of one copy of the RET ligand Gdnf rescues Fat4 kidney development, supporting the proposal that loss of Fat4 hyperactivates RET signaling. Conditional knockout analyses revealed a non-autonomous role for Fat4 in regulating RET signaling. Mechanistically, we found that FAT4 interacts with RET through extracellular cadherin repeats. Importantly, expression of FAT4 perturbs the assembly of the RET-GFRA1-GDNF complex, reducing RET signaling. Thus, FAT4 interacts with RET to fine-tune RET signaling, establishing a juxtacrine mechanism controlling kidney development.
FAT4 突变导致多种人类疾病，扰乱肾脏的正常发育。然而，其潜在机制仍不清楚。在研究 FAT4 在小鼠中缺失时观察到的双肾表型时，我们发现非典型钙黏蛋白 FAT4 与 RET 之间存在相互作用，RET 是一种酪氨酸激酶受体，对肾脏发育至关重要。对 Fat4 肾脏发育的分析显示输尿管芽异常出芽和 RET 信号过度激活。去除 RET 配体 Gdnf 的一个拷贝可挽救 Fat4 肾脏发育，支持 Fat4 缺失过度激活 RET 信号的假说。条件性敲除分析显示 Fat4 在调节 RET 信号中具有非自主作用。从机制上讲，我们发现 FAT4 通过细胞外钙黏蛋白重复与 RET 相互作用。重要的是，FAT4 的表达扰乱了 RET-GFRA1-GDNF 复合物的组装，从而降低了 RET 信号。因此，FAT4 通过与 RET 相互作用来精细调节 RET 信号，建立了一种旁分泌机制来控制肾脏发育。
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