Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease [P15]

Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for development, fibrosis, and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis, and identifies new therapeutic targets for patients with renal centrosomopathies. to identify the pathways that cause the fibrotic and cystic disease phenotypes upon Cep120 loss, Kidneys were collected from Hoxb7-Cep120 KO and WT mice at P15; also, we compared the signaling pathways that are disrupted in cystic kidneys following Cep120 loss versus ciliary signaling (Pkd1-KO), using bulk RNA-seq analysis of kidneys isolated from Hoxb7-Pkd1 KO mice at P15

破坏中心体（centrosome）生成或功能的突变会引发先天性肾脏发育缺陷与纤维囊性病变。然而，中心体功能异常如何导致肾脏疾病表型的具体机制仍未阐明。本研究聚焦小鼠胚胎肾的肾单位及集合管祖细胞微环境，探究了中心体复制必需的纤毛病（ciliopathy）基因Cep120条件性敲除所产生的生物学效应。研究结果显示，Cep120缺失会导致帽状间充质与输尿管芽两种细胞群的丰度显著降低，该现象是有丝分裂延迟、细胞凋亡增加以及祖细胞过早分化共同作用的结果。上述缺陷会使新生小鼠出现肾脏发育不良，随后迅速形成囊肿，表现出间质纤维化加重与肾功能下降的特征。对Cep120基因缺失型小鼠的胚胎及出生后肾脏进行RNA测序（RNA sequencing），鉴定出了与发育、纤维化及囊肿形成密切相关的通路表达变化。本研究明确了肾脏形态发生过程中中心体功能异常所引发的细胞与发育缺陷，并为肾脏中心体病（renal centrosomopathies）患者找到了全新的治疗靶点。为鉴定Cep120缺失后引发纤维囊性疾病表型的核心通路，本研究收集了出生后第15天（P15）的Hoxb7-Cep120敲除（KO）与野生型（WT）小鼠肾脏；同时，通过对出生后第15天Hoxb7-Pkd1敲除小鼠的肾脏开展批量RNA测序（bulk RNA-seq）分析，对比了Cep120缺失所致囊性肾脏与纤毛信号通路异常（Pkd1-KO）的受损信号通路差异。