Identification of Annexin A4 as a hepatopancreas factor involved in liver cell survival.
Identification of Annexin A4 as a hepatopancreas factor involved in liver cell survival.
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DOI：
10.1016/j.ydbio.2014.08.025
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发表时间：
2014-11-01
影响因子：
2.7
通讯作者：
Dong, P. Duc Si
中科院分区：
文献类型：
--
作者：
Zhang, Danhua;Golubkov, Vladislav S.;Han, Wenlong;Correa, Ricardo G.;Zhou, Ying;Lee, Sunyoung;Strongin, Alex Y.;Dong, P. Duc Si
为了深入了解肝脏和胰腺的发育，我们研究了2F11的靶标，2F11是一种未知抗原的单抗，广泛用于斑马鱼研究中标记肝胰管。利用质谱仪和体内实验，我们确定了2F11的分子靶点为钙结合蛋白Annexin A4(Anxa4)。我们进一步发现，在斑马鱼和小鼠内胚层中，Anxa4在发育中的肝脏和胰腺中广泛表达，后来变得更加局限于肝胰管和胰岛，包括产生胰岛素的β细胞。虽然Anxa4是几个单基因糖尿病基因的已知靶点，它的高表达与恶性肿瘤的化疗耐药有关，但它在体内的作用在很大程度上还没有被探索。在斑马鱼中敲除Anxa4基因后，Caspase8和Δ113P53的表达增加，Caspase3的肝芽特异性激活和细胞凋亡。马赛克基因敲除表明，Anxa4在肝芽中是细胞自主生存所必需的。这一发现进一步得到了使用CRISPR/Cas9系统的马赛克anxa4基因敲除研究的证实。总的来说，我们认为Anxa4是一种新的、进化上保守的肝胰脏因子，斑马鱼通过抑制外源性凋亡途径来维持肝脏祖细胞的活力。Anxa4在细胞存活中的作用可能与糖尿病β细胞凋亡和癌细胞化疗耐药的机制有关。
To gain insight into liver and pancreas development, we investigated the target of 2F11, a monoclonal antibody of unknown antigen, widely used in zebrafish studies for labeling hepatopancreatic ducts. Utilizing mass spectrometry and in vivo assays, we determined the molecular target of 2F11 to be Annexin A4 (Anxa4), a calcium binding protein. We further found that in both zebrafish and mouse endoderm, Anxa4 is broadly expressed in the developing liver and pancreas, and later becomes more restricted to the hepatopancreatic ducts and pancreatic islets, including the insulin producing β-cells. Although Anxa4 is a known target of several monogenic diabetes genes and its elevated expression is associated with chemoresistance in malignancy, its in vivo role is largely unexplored. Knockdown of Anxa4 in zebrafish leads to elevated expression of caspase 8 and Δ113p53, and liver bud specific activation of Caspase 3 and apoptosis. Mosaic knockdown reveal that Anxa4 is required cell-autonomously in the liver bud for cell survival. This finding is further corroborated with mosaic anxa4 knockout studies using the CRISPR/Cas9 system. Collectively, we identify Anxa4 as a new, evolutionarily conserved hepatopancreatic factor that is required in zebrafish for liver progenitor viability, through inhibition of the extrinsic apoptotic pathway. A role for Anxa4 in cell survival may have implications for the mechanism of diabetic β-cell apoptosis and cancer cell chemoresistance.
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影响因子：
7
作者：
Farber, SA;De Rose, RA;Halpern, ME
通讯作者：
Halpern, ME
影响因子：
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作者：
Delous M;Yin C;Shin D;Ninov N;Debrito Carten J;Pan L;Ma TP;Farber SA;Moens CB;Stainier DY
通讯作者：
Stainier DY
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46.9
作者：
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影响因子：
8.8
作者：
Duncan, R.;Carpenter, B.;Main, L. C.;Telfer, C.;Murray, G. I.
通讯作者：
Murray, G. I.
影响因子：
2.7
作者：
Anderson, Ryan M.;Bosch, Justin A.;Goll, Mary G.;Hesselson, Daniel;Dong, P. Duc Si;Shin, Donghun;Chi, Neil C.;Shin, Chong Hyun;Schlegel, Amnon;Halpern, Marnie;Stainier, Didier Y. R.
通讯作者：
Stainier, Didier Y. R.