Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis
Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis
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DOI：
10.1093/hmg/ddp149
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发表时间：
2009-06-15
影响因子：
3.5
通讯作者：
Cheadle, Jeremy P.
中科院分区：
文献类型：
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作者：
Bonnet, Cleo S.;Aldred, Mark;Cheadle, Jeremy P.
使用mTOR抑制剂治疗结节性硬化症(TSC)相关肿瘤的临床试验正在进行中。在这里，我们显示了许多来自TSC1(+/-)和TSC2(+/-)小鼠的早期肾脏病变没有表现出mTOR激活，这表明可能有必要通过药物靶向替代途径来防止肿瘤的形成。常染色体显性遗传性多囊肾病(ADPKD)1基因(PKD1)遗传缺失的患者常发展为肾囊肿，并发展为严重的、发病早的多囊肾。利用小鼠模型，我们显示了TSC1和TSC2与PKD1之间的遗传相互作用，并证实了肾脏囊变的mTOR非依赖途径。我们观察到TSC和PKD1基因产物有助于调节初级纤毛长度，并与该细胞器调节细胞极性的功能一致，发现许多来自TSC1、TSC2和PKD1杂合子小鼠的囊前肾小管和肝胆管细胞的分裂高度定向错误。因此，我们认为细胞极性缺陷是TSC和ADPKD相关囊性疾病的基础，靶向这一途径可能是关键的治疗益处。
Clinical trials are underway for the treatment of tuberous sclerosis (TSC)-associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1(+/-) and Tsc2(+/-) mice do not exhibit mTOR activation, suggesting that pharmacological targeting of an alternative pathway may be necessary to prevent tumour formation. Patients with TSC often develop renal cysts and those with inherited co-deletions of the autosomal dominant polycystic kidney disease (ADPKD) 1 gene (PKD1) develop severe, early onset, polycystic kidneys. Using mouse models, we showed a genetic interaction between Tsc1 and Tsc2 with Pkd1 and confirmed an mTOR-independent pathway of renal cystogenesis. We observed that the Tsc and Pkd1 gene products helped regulate primary cilia length and, consistent with the function of this organelle in modulating cell polarity, found that many dividing pre-cystic renal tubule and hepatic bile duct cells from Tsc1, Tsc2 and Pkd1 heterozygous mice were highly misoriented. We therefore propose that defects in cell polarity underlie TSC and ADPKD-associated cystic disease and targeting of this pathway may be of key therapeutic benefit.