A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity.
A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity.
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DOI：
10.1371/journal.pgen.1002766
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Andrews GK
中科院分区：
文献类型：
--
作者：
Geiser J;Venken KJ;De Lisle RC;Andrews GK
人类Zip 4基因突变导致肠病性肢端皮炎，这是一种罕见的假显性致死性遗传疾病。我们在小鼠中建立了一种他莫昔芬诱导的肠细胞特异性敲除该基因的方法，模拟了这种人类疾病。我们发现，小鼠的肠上皮细胞Zip 4基因在整个生命过程中都是必不可少的，除非对小鼠进行护理或提供过量的膳食锌，否则该基因的功能丧失会迅速导致消耗和死亡。敲除的最初效果是潘氏细胞的重编程，这有助于隐窝中的肠道干细胞生态位。潘氏细胞中不稳定的锌丢失，随后减少Sox 9（性别决定区Y-盒9）和溶菌酶表达，以及粘蛋白的积累，这通常在杯状细胞中发现。这伴随着肠隐窝发育不良和小肠细胞分裂显著减少，绒毛肠上皮细胞中mTOR 1活性减弱，表明分解代谢增加，蛋白质合成减少。随后是吸收上皮的解体。Zip 4肠基因敲除小鼠的小肠、肝脏和胰腺的元素分析显示，随着疾病的进展，这些器官中的总锌急剧迅速下降，而铁、锰和铜在肝脏中缓慢积累到高水平。这些研究强烈表明，肠病性肢端皮炎患者的消瘦和致死性反映了肠锌转运蛋白ZIP 4的功能丧失，这导致潘氏细胞基因表达异常，肠干细胞生态位破坏和肠粘膜功能减弱。这些变化，反过来，导致从合成代谢到分解代谢的转换和几种必需金属的稳态改变，如果不通过过量的饮食锌治疗，会导致体重急剧下降和死亡。小鼠肠道中锌转运蛋白ZIP 4的功能丧失模拟了致命的人类肠病性肢端皮炎。这是一种罕见的人类疾病，目前还不清楚。我们的研究证明了肠道中ZIP 4在这种疾病中的至关重要性，并揭示了致死性的根本原因是肠道干细胞生态位的破坏和小肠功能的受损。这反过来会导致体重急剧下降和死亡，除非用外源性锌治疗。
Mutations in the human Zip4 gene cause acrodermatitis enteropathica, a rare, pseudo-dominant, lethal genetic disorder. We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder. We found that the enterocyte Zip4 gene in mice is essential throughout life, and loss-of-function of this gene rapidly leads to wasting and death unless mice are nursed or provided excess dietary zinc. An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts. Labile zinc in Paneth cells was lost, followed by diminished Sox9 (sex determining region Y-box 9) and lysozyme expression, and accumulation of mucin, which is normally found in goblet cells. This was accompanied by dysplasia of the intestinal crypts and significantly diminished small intestine cell division, and attenuated mTOR1 activity in villus enterocytes, indicative of increased catabolic metabolism, and diminished protein synthesis. This was followed by disorganization of the absorptive epithelium. Elemental analyses of small intestine, liver, and pancreas from Zip4-intestine knockout mice revealed that total zinc was dramatically and rapidly decreased in these organs whereas iron, manganese, and copper slowly accumulated to high levels in the liver as the disease progressed. These studies strongly suggest that wasting and lethality in acrodermatitis enteropathica patients reflects the loss-of-function of the intestine zinc transporter ZIP4, which leads to abnormal Paneth cell gene expression, disruption of the intestinal stem cell niche, and diminished function of the intestinal mucosa. These changes, in turn, cause a switch from anabolic to catabolic metabolism and altered homeostasis of several essential metals, which, if untreated by excess dietary zinc, leads to dramatic weight loss and death. Loss-of-function of the zinc transporter ZIP4 in the mouse intestine mimics the lethal human disease acrodermatitis enteropathica. This is a rare disease in humans that is not well understood. Our studies demonstrate the paramount importance of ZIP4 in the intestine in this disease and reveal that a root cause of lethality is disruption of the intestine stem cell niche and impaired function of the small intestine. This, in turn, leads to dramatic weight loss and death unless treated with exogenous zinc.
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影响因子：
7.3
作者：
ELMES, ME
通讯作者：
ELMES, ME
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
4.7
作者：
Beharier, Ofer;Dror, Shani;Etzion, Yoram
通讯作者：
Etzion, Yoram
影响因子：
3.5
作者：
Dufner-Beattie, Jodi;Weaver, Benjamin P.;Andrews, Glen K.
通讯作者：
Andrews, Glen K.
DOI：
10.1016/0960-0760(93)90160-x
发表时间：
1993-06-01
影响因子：
4.1
作者：
DAS, SK;PARIA, BC;DEY, SK
通讯作者：
DEY, SK