Mavropoulos Anastasia, Devos Nathalie, Biemar Frédéric, Zecchin Elisabetta, Argenton Francesco, Edlund Helena, Motte Patrick, Martial Joseph A, Peers Bernard
Laboratoire de Biologie Moléculaire et de Génie Génétique, Center of Biomedical Integrative Genoproteomics (CBIG), Université de Liège, Institut de Chimie, Bâtiment B6, 4000 Liège (Sart-Tilman), Belgium.
Dev Biol. 2005 Sep 1;285(1):211-23. doi: 10.1016/j.ydbio.2005.06.024.
Pancreas development relies on a network of transcription factors belonging mainly to the Homeodomain and basic Helix-Loop-Helix families. We show in this study that, in zebrafish, sox4, a member of the SRY-like HMG-box (SOX) family, is required for proper endocrine cell differentiation. We found that two genes orthologous to mammalian Sox4 are present in zebrafish and that only one of them, sox4b, is strongly expressed in the pancreatic anlage. Transcripts of sox4b were detected in mid-trunk endoderm from the 5-somite stage, well before the onset of expression of the early pancreatic gene pdx-1. Furthermore, by fluorescent double in situ hybridization, we found that expression of sox4b is mostly restricted to precursors of the endocrine compartment. This expression is not maintained in differentiated cells although transient expression can be detected in alpha cells and some beta cells. That sox4b-expressing cells belong to the endocrine lineage is further illustrated by their absence from the pancreata of slow-muscle-omitted mutant embryos, which specifically lack all early endocrine markers while retaining expression of exocrine markers. The involvement of sox4b in cell differentiation is suggested firstly by its up-regulation in mind bomb mutant embryos displaying accelerated pancreatic cell differentiation. In addition, sox4b knock-down leads to a drastic reduction in glucagon expression, while other pancreatic markers including insulin, somatostatin, and trypsin are not significantly affected. This disruption of alpha cell differentiation is due to down-regulation of the homeobox arx gene specifically in the pancreas. Taken together, these data demonstrate that, in zebrafish, sox4b is expressed transiently during endocrine cell differentiation and plays a crucial role in the generation of alpha endocrine cells.
胰腺发育依赖于一个主要属于同源结构域和基本螺旋-环-螺旋家族的转录因子网络。我们在本研究中表明，在斑马鱼中，SRY样HMG盒（SOX）家族成员sox4是正常内分泌细胞分化所必需的。我们发现斑马鱼中有两个与哺乳动物Sox4直系同源的基因，其中只有一个，即sox4b，在胰腺原基中强烈表达。在5体节期的中躯干内胚层中检测到sox4b的转录本，远早于早期胰腺基因pdx-1表达的开始。此外，通过荧光双原位杂交，我们发现sox4b的表达主要局限于内分泌区室的前体细胞。尽管在α细胞和一些β细胞中可以检测到瞬时表达，但在分化细胞中这种表达并不持续。慢肌缺失突变胚胎的胰腺中没有表达sox4b的细胞，这进一步说明了表达sox4b的细胞属于内分泌谱系，这些突变胚胎特异性地缺乏所有早期内分泌标记物，同时保留外分泌标记物的表达。sox4b参与细胞分化首先表现在其在显示加速胰腺细胞分化的mind bomb突变胚胎中上调。此外，敲低sox4b会导致胰高血糖素表达急剧减少，而其他胰腺标记物，包括胰岛素、生长抑素和胰蛋白酶，没有受到显著影响。α细胞分化的这种破坏是由于胰腺中同源框arx基因的下调所致。综上所述，这些数据表明，在斑马鱼中，sox4b在内分泌细胞分化过程中瞬时表达，并在α内分泌细胞的产生中起关键作用。
