Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9.
Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9.
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DOI：
10.1053/j.gastro.2009.02.051
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发表时间：
2009-06
期刊：
影响因子：
29.4
通讯作者：
Lemaigre FP
中科院分区：
文献类型：
--
作者：
Antoniou A;Raynaud P;Cordi S;Zong Y;Tronche F;Stanger BZ;Jacquemin P;Pierreux CE;Clotman F;Lemaigre FP
许多疾病的特征在于肝内胆管的缺陷形成。在胚胎中，成肝细胞分化为胆管细胞，胆管细胞产生肝内胆管。在这里，我们研究了这些导管如何在小鼠肝脏中发育，并描述了转录因子SOX 9的作用。我们将SOX 9鉴定为一种新的胆管标记物，并将其与其他细胞标记物一起用于免疫染色实验以表征胆管形态发生的过程。通过原位杂交和免疫组化方法测定生长因子的表达，并在培养的胚胎成肝细胞上研究其作用。Sox 9功能通过具有Sox 9的肝脏特异性失活的表型小鼠来研究。胆管形成开始于形成不对称的导管结构，在门静脉侧由胆管细胞排列，在实质侧由肝母细胞排列。当导管从门部向外周生长时，衬在不对称结构上的成肝细胞分化为胆管细胞，从而形成仅衬有胆管细胞的对称导管。我们还提供了TGFβ促进衬在不对称结构上的成肝细胞分化的证据。在没有S 0X 9的情况下，不对称结构成熟为对称导管被延迟。这与C/EBPα和HES 1以及TGFβ受体II型的异常表达有关，它们是胆道发育的调节因子。我们的研究结果表明，胆道发展的进展，根据一种新的模式tubulogenesis的特点是短暂的不对称性，其时间是由SOX 9控制。
A number of diseases are characterized by defective formation of the intrahepatic bile ducts. In the embryo, hepatoblasts differentiate to cholangiocytes which give rise to the intrahepatic bile ducts. Here we investigated how these ducts develop in mouse liver and characterized the role of the transcription factor SOX9. We identified SOX9 as a new biliary marker and used it with other cell markers in immunostaining experiments to characterize the process of bile duct morphogenesis. The expression of growth factors was determined by in situ hybridization and immunostaining, and their role was studied on cultured embryonic hepatoblasts. SOX9 function was investigated by phenotyping mice with a liver-specific inactivation of Sox9. Biliary tubulogenesis started with formation of asymmetrical ductal structures, lined on the portal side by cholangiocytes and on the parenchymal side by hepatoblasts. When the ducts grew from the hilum to the periphery, the hepatoblasts lining the asymmetrical structures differentiated to cholangiocytes, thereby allowing formation of symmetrical ducts lined only by cholangiocytes. We also provide evidence that TGFβ promotes differentiation of the hepatoblasts lining the asymmetrical structures. In the absence of SOX9, the maturation of asymmetrical structures into symmetrical ducts was delayed. This was associated with abnormal expression of C/EBPα and HES1, as well as of the TGFβ receptor type II, which are regulators of biliary development. Our results suggest that biliary development proceeds according to a new mode of tubulogenesis characterized by transient asymmetry and whose timing is controlled by SOX9.
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