Murtaugh L Charles, Law Anica C, Dor Yuval, Melton Douglas A
Department of Molecular and Cellular Biology and Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
Development. 2005 Nov;132(21):4663-74. doi: 10.1242/dev.02063. Epub 2005 Sep 28.
Despite our increasingly sophisticated understanding of transcriptional regulation in pancreas development, we know relatively little about the extrinsic signaling pathways involved in this process. We show here that the early pancreatic epithelium exhibits a specific enrichment in unphosphorylated beta-catenin protein, a hallmark of activation of the canonical Wnt signaling pathway. To determine if this pathway is functionally required for normal pancreas development, we have specifically deleted the beta-catenin gene in these cells. Pancreata developing without beta-catenin are hypoplastic, although their early progenitors appear normal and exhibit no premature differentiation or death. Surprisingly, and in marked contrast to its role in the intestine, loss of beta-catenin does not significantly perturb islet endocrine cell mass or function. The major defect of the beta-catenin-deficient pancreas is an almost complete lack of acinar cells, which normally comprise the majority of the organ. beta-Catenin appears to be cell-autonomously required for the specification of acinar cells, rather than for their survival or maintenance, as deletion of beta-catenin specifically in differentiated acinar cells has no effect. Thus, our data are consistent with a crucial role for canonical Wnt signals in acinar lineage specification and differentiation.
尽管我们对胰腺发育过程中转录调控的理解日益深入，但对于参与这一过程的外在信号通路却知之甚少。我们在此表明，早期胰腺上皮细胞中未磷酸化的β-连环蛋白水平显著升高，这是经典Wnt信号通路激活的标志。为了确定该信号通路是否为胰腺正常发育所必需，我们在这些细胞中特异性敲除了β-连环蛋白基因。缺乏β-连环蛋白的胰腺发育不全，尽管其早期祖细胞看起来正常，且未出现过早分化或死亡。令人惊讶的是，与它在肠道中的作用形成鲜明对比的是，β-连环蛋白的缺失并未显著影响胰岛内分泌细胞的数量或功能。β-连环蛋白缺陷型胰腺的主要缺陷是几乎完全缺乏腺泡细胞，而腺泡细胞通常构成该器官的大部分。β-连环蛋白似乎是腺泡细胞特化所必需的，而非其存活或维持所必需，因为在已分化的腺泡细胞中特异性敲除β-连环蛋白并无影响。因此，我们的数据表明经典Wnt信号在腺泡细胞谱系特化和分化中起关键作用。
