PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
复制标题
DOI：
--
复制
发表时间：
1996-03
期刊：
影响因子：
4.6
通讯作者：
M. F. Offield;T. Jetton;P. Labosky;M. Ray;R. Stein;M. Magnuson;B. Hogan;C. Wright
中科院分区：
文献类型：
--
作者：
M. F. Offield;T. Jetton;P. Labosky;M. Ray;R. Stein;M. Magnuson;B. Hogan;C. Wright
已经提出爪蟾同源框基因XlHbox 8参与胰腺和十二指肠发育期间的内胚层分化（Wright，C.V.E.，Schnegelsberg，P.和De Robertis，E.M.（1988年）。Development 105，787-794）。为了直接测试该假设，使用基因靶向在小鼠XlHbox 8同源物pdx-1中产生两种不同的无效突变。在第一个中，第二个pdx-1外显子，包括同源框，被新霉素抗性盒取代。在第二个中，lacZ报告基因与PDX-1的N末端框内融合，取代了大部分同源结构域。新生的pdx-1 -/-小鼠是无胰腺的，证实了先前的报道（Jonsson，J.，卡尔森，L.，Edlund，T.和Edlund，H.（1994年）。Nature 371，606-609）。然而，胰腺芽在纯合突变体中确实形成，并且背芽经历有限的增殖和生长以形成小的、不规则分支的导管树。这种生长不含胰岛素或淀粉酶阳性细胞，但发现胰高血糖素表达细胞。十二指肠吻侧显示正常柱状上皮衬里、绒毛和Brunner腺的局部缺失，被类似胆管衬里的GLUT 2阳性立方上皮所取代。就在异常上皮的远端，绒毛中的肠内分泌细胞数量大大减少。PDX-1/β-半乳糖苷酶融合等位基因在不存在功能性PDX-1的情况下在胰腺和十二指肠细胞中表达，表达持续到围产期，具有相似的边界和表达水平。这些结果为pdx-1在后前肠的决定和分化中的作用提供了额外的见解，特别是关于胰腺祖细胞的增殖和分化。
It has been proposed that the Xenopus homeobox gene, XlHbox8, is involved in endodermal differentiation during pancreatic and duodenal development (Wright, C.V.E., Schnegelsberg, P. and De Robertis, E.M. (1988). Development 105, 787-794). To test this hypothesis directly, gene targeting was used to make two different null mutations in the mouse XlHbox8 homolog, pdx-1. In the first, the second pdx-1 exon, including the homeobox, was replaced by a neomycin resistance cassette. In the second, a lacZ reporter was fused in-frame with the N terminus of PDX-1, replacing most of the homeodomain. Neonatal pdx-1 -/- mice are apancreatic, in confirmation of previous reports (Jonsson, J., Carlsson, L., Edlund, T. and Edlund, H. (1994). Nature 371, 606-609). However, the pancreatic buds do form in homozygous mutants, and the dorsal bud undergoes limited proliferation and outgrowth to form a small, irregularly branched, ductular tree. This outgrowth does not contain insulin or amylase-positive cells, but glucagon-expressing cells are found. The rostral duodenum shows a local absence of the normal columnar epithelial lining, villi, and Brunner's glands, which are replaced by a GLUT2-positive cuboidal epithelium resembling the bile duct lining. Just distal of the abnormal epithelium, the numbers of enteroendocrine cells in the villi are greatly reduced. The PDX-1/beta-galactosidase fusion allele is expressed in pancreatic and duodenal cells in the absence of functional PDX-1, with expression continuing into perinatal stages with similar boundaries and expression levels. These results offer additional insight into the role of pdx-1 in the determination and differentiation of the posterior foregut, particularly regarding the proliferation and differentiation of the pancreatic progenitors.