Sox9b is a key regulator of pancreaticobiliary ductal system development.
Sox9b is a key regulator of pancreaticobiliary ductal system development.
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DOI：
10.1371/journal.pgen.1002754
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Stainier DY
中科院分区：
文献类型：
--
作者：
Delous M;Yin C;Shin D;Ninov N;Debrito Carten J;Pan L;Ma TP;Farber SA;Moens CB;Stainier DY
胰胆管系统将肝脏和胰腺与肠道连接起来。它由肝胰管系统以及肝内胆管和胰内胆管组成。尽管胰胆管系统具有重要的生理意义，但对其发育仍知之甚少。SRY相关转录因子SOX9在哺乳动物的胰胆管系统中表达，但Sox9杂合子小鼠的围生期致死性使功能丧失分析具有挑战性。我们转向斑马鱼来评估SOX9在胰胆管系统发育中的作用。我们首先证明斑马鱼sox9b概括了小鼠sox9在胰胆管系统中的表达模式，并使用sox9b的无意义等位基因sox9bfh313来剖析其在这一结构的形态发生中的功能。值得注意的是，sox9bfh313纯合子突变体可以存活到成年，并表现出与肝和胰管增殖、囊肿形成和纤维化相关的胆汁淤积。对sox9bfh313突变胚胎和幼虫的分析表明，HPD细胞似乎错误地分化为肝脏和/或胰腺命运，导致结构畸形。肝内胆管细胞是特定的，但不能组装成一个功能网络。同样，在sox9bfh313突变体中，胰腺内导管的形成严重受损，而胚胎的内分泌和腺泡间隔似乎没有受到影响。突变体sox9bfh313的肝内和胰内导管缺陷在幼虫期和幼虫期恶化，促使成虫表型。我们进一步证明了Sox9b与Notch信号相互作用来调节肝内胆管网络的形成：Sox9b的表达受Notch信号的正向调节，而Sox9b的功能是维持肝内胆管细胞中的Notch信号所必需的。总之，这些数据揭示了SOX9在胰胆管系统的形态发生中的关键作用，并表明人类SOX9是胰胆管畸形相关病理的候选基因。肝脏和胰腺的功能分别是分泌胆汁和胰液的外分泌腺，以帮助消化和吸收营养。这些液体通过胰胆管系统到达肠道，胰胆管系统是一个复杂的管道网络。尽管它起着关键作用，但人们对这一导管系统的发展知之甚少。我们发现斑马鱼转录因子基因sox9b和它的哺乳动物同源基因一样，在胰胆管系统中特异表达。Sox9杂合小鼠的围产期致死性使得SOX9的功能分析具有挑战性；因此，我们转向斑马鱼来分析SOX9在胰胆管系统发育中的作用。我们发现，活到成年的斑马鱼sox9b突变体在这种导管网络的形态发生上存在缺陷：肝脏内和胰腺内的导管未能形成分支网络，而连接肝脏和胰腺与肠道的导管畸形。这些胆管缺陷影响胆汁的运输，并导致成年突变鱼的胆汁淤积。在分子水平上，Sox9b与Notch信号通路相互作用，调控肝内胆管网络的发育。因此，我们在斑马鱼中的研究揭示了SOX9在胰胆管系统形态发生中广泛而复杂的作用。
The pancreaticobiliary ductal system connects the liver and pancreas to the intestine. It is composed of the hepatopancreatic ductal (HPD) system as well as the intrahepatic biliary ducts and the intrapancreatic ducts. Despite its physiological importance, the development of the pancreaticobiliary ductal system remains poorly understood. The SRY-related transcription factor SOX9 is expressed in the mammalian pancreaticobiliary ductal system, but the perinatal lethality of Sox9 heterozygous mice makes loss-of-function analyses challenging. We turned to the zebrafish to assess the role of SOX9 in pancreaticobiliary ductal system development. We first show that zebrafish sox9b recapitulates the expression pattern of mouse Sox9 in the pancreaticobiliary ductal system and use a nonsense allele of sox9b, sox9bfh313, to dissect its function in the morphogenesis of this structure. Strikingly, sox9bfh313 homozygous mutants survive to adulthood and exhibit cholestasis associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis. Analysis of sox9bfh313 mutant embryos and larvae reveals that the HPD cells appear to mis-differentiate towards hepatic and/or pancreatic fates, resulting in a dysmorphic structure. The intrahepatic biliary cells are specified but fail to assemble into a functional network. Similarly, intrapancreatic duct formation is severely impaired in sox9bfh313 mutants, while the embryonic endocrine and acinar compartments appear unaffected. The defects in the intrahepatic and intrapancreatic ducts of sox9bfh313 mutants worsen during larval and juvenile stages, prompting the adult phenotype. We further show that Sox9b interacts with Notch signaling to regulate intrahepatic biliary network formation: sox9b expression is positively regulated by Notch signaling, while Sox9b function is required to maintain Notch signaling in the intrahepatic biliary cells. Together, these data reveal key roles for SOX9 in the morphogenesis of the pancreaticobiliary ductal system, and they cast human Sox9 as a candidate gene for pancreaticobiliary duct malformation-related pathologies. The liver and pancreas function as exocrine glands that secrete bile and pancreatic juice, respectively, to aid the digestion and absorption of nutrients. These fluids reach the intestine via the pancreaticobiliary ductal system, a complex network of ducts. Despite its pivotal role, the development of this ductal system is poorly understood. We have discovered that the zebrafish transcription factor gene sox9b, like its mammalian ortholog, is specifically expressed in the pancreaticobiliary ductal system. The perinatal lethality of Sox9 heterozygous mice makes the analysis of SOX9 function challenging; thus, we turned to the zebrafish to analyze the role of SOX9 in pancreaticobiliary ductal system development. We found that zebrafish sox9b mutants, which survive to adulthood, display defects in the morphogenesis of this ductal network: the intrahepatic and intrapancreatic ducts fail to form a branched network, whereas the ducts connecting the liver and pancreas to the intestine are malformed. These ductal defects affect bile transport and lead to cholestasis in adult mutant fish. At the molecular level, Sox9b interacts with the Notch signaling pathway to regulate the development of the intrahepatic biliary network. Therefore, our work in zebrafish reveals a broad and complex role for SOX9 in pancreaticobiliary ductal system morphogenesis.
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影响因子：
11.8
作者：
Chung, Won-Suk;Shin, Chong Hyun;Stainier, Didier Y. R.
通讯作者：
Stainier, Didier Y. R.
影响因子：
4.6
作者：
Hofmann, Jennifer J.;Zovein, Ann C.;Iruela-Arispe, M. Luisa
通讯作者：
Iruela-Arispe, M. Luisa
DOI：
10.1073/pnas.111092198
发表时间：
2001-06-05
影响因子：
11.1
作者：
Bi, WM;Huang, WD;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
DOI：
10.1002/dvdy.22220
发表时间：
2010-03
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
--
作者：
Lorent K;Moore JC;Siekmann AF;Lawson N;Pack M
通讯作者：
Pack M
影响因子：
29.4
作者：
Kodama, Y;Hijikata, M;Chiba, T
通讯作者：
Chiba, T