Heller R S, Stoffers D A, Hussain M A, Miller C P, Habener J F
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA.
Gastroenterology. 1998 Aug;115(2):381-7. doi: 10.1016/s0016-5085(98)70204-5.
BACKGROUND & AIMS: The endoderm-specific homeodomain transcription factor IDX-1 is critical for pancreas development and for the regulation of islet cell-specific genes. During development, IDX-1 is expressed in the epithelial cells of the endoderm in the pancreatic anlage of the foregut. The aim of this study was to determine whether IDX-1 may have potential properties of a master homeotic determinant of pancreas and/or gut development.
Transgenic mice were generated in which the expression of IDX-1 was misdirected by a promoter of the mesoderm-specific homeodomain protein Hoxa-4 known to express in the stomach and hindgut during development. The expectation was the formation of ectopic pancreatic tissue or alterations of gut patterning or morphology.
Although no ectopic induction of pancreatic markers was found in these transgenic mice, they manifested an altered midgut-hindgut union and agenesis of the cecum. Further, IDX-1 binds to the gut-specific homeodomain protein Cdx-2 and inhibits transactivation of the sucrase-isomaltase promoter by Cdx-2.
These findings further support the emerging understanding that interactions among different classes of homeodomain proteins, expressed in a spatially and temporally restricted manner during development, determine the pattern of organogenesis. A possible mechanism for the dysmorphogenesis of the proximal colon may be an inhibition of Cdx-2 actions by IDX-1.
内胚层特异性同源结构域转录因子IDX-1对胰腺发育及胰岛细胞特异性基因的调控至关重要。在发育过程中，IDX-1在前肠胰腺原基的内胚层上皮细胞中表达。本研究旨在确定IDX-1是否可能具有胰腺和/或肠道发育的主要同源异型决定因子的潜在特性。
构建转基因小鼠，其中IDX-1的表达由中胚层特异性同源结构域蛋白Hoxa-4的启动子错误引导，已知该蛋白在发育过程中在胃和后肠中表达。预期会形成异位胰腺组织或肠道模式或形态的改变。
虽然在这些转基因小鼠中未发现胰腺标志物的异位诱导，但它们表现出中肠-后肠结合改变和盲肠发育不全。此外，IDX-1与肠道特异性同源结构域蛋白Cdx-2结合，并抑制Cdx-2对蔗糖酶-异麦芽糖酶启动子的反式激活。
这些发现进一步支持了一种新的认识，即在发育过程中以空间和时间受限方式表达的不同类别的同源结构域蛋白之间的相互作用决定了器官发生的模式。近端结肠畸形发生的一种可能机制可能是IDX-1对Cdx-2作用的抑制。
