Connective Tissue Growth Factor (CTGF) Inactivation Leads to Defects in Islet Cell Lineage Allocation and β-Cell Proliferation during Embryogenesis
Connective Tissue Growth Factor (CTGF) Inactivation Leads to Defects in Islet Cell Lineage Allocation and β-Cell Proliferation during Embryogenesis
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DOI：
10.1210/me.2008-0045
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发表时间：
2009-03-01
影响因子：
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通讯作者：
Gannon, Maureen
中科院分区：
文献类型：
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作者：
Crawford, Laura A.;Guney, Michelle A.;Gannon, Maureen
正常胰岛形态发生所必需的因素尚未得到很好的表征。在这里，我们报告，结缔组织生长因子（CTGF）参与建立正常的胰岛内分泌细胞的比例和建筑。CTGF是一种分泌蛋白，已知可调节几种生长因子信号传导途径，包括TGF-β、BMP和Wnt。尽管其在胰腺疾病如胰腺炎和胰腺癌中的作用已被充分证明，但CTGF在正常胰腺发育和功能中的作用迄今尚未被研究。使用lacZ标记的CTGF等位基因，我们首次描述了CTGF在发育中的胰腺中的表达模式以及CTGF对正常胰岛形态发生和胚胎β细胞增殖的需求。CTGF在胰腺导管上皮和血管内皮中高度表达，并且在发育中的胰岛素（+）细胞中以较低水平表达，但在出生后不久在β细胞中下调。来自CTGF缺失胚胎的胰腺具有胰高血糖素（+）细胞的增加，伴随着胰岛素（+）细胞的减少，并且显示出胰岛形态发生的缺陷。CTGF的缺失还导致妊娠晚期β细胞增殖的急剧减少。与CTGF缺失胚胎不同，CTGF杂合子在出生后存活，并表现出一系列胰岛表型，包括胰岛细胞类型的混合，胰高血糖素（+）细胞数量增加和β细胞肥大。（分子内分泌学23：324-336，2009）
The factors necessary for normal pancreatic islet morphogenesis have not been well characterized. Here we report that connective tissue growth factor ( CTGF) is involved in the establishment of normal islet endocrine cell ratio and architecture. CTGF is a secreted protein known to modulate several growth factor-signaling pathways including TGF-beta, BMP, and Wnt. Although its role in pancreatic diseases such as pancreatitis and pancreatic cancer are well documented, a role for CTGF in normal pancreas development and function has heretofore not been examined. Using a lacZ-tagged CTGF allele, we describe for the first time the expression pattern of CTGF in the developing pancreas and the requirement of CTGF for normal islet morphogenesis and embryonic beta-cell proliferation. CTGF is highly expressed in pancreatic ductal epithelium and vascular endothelium, as well as at lower levels in developing insulin(+) cells, but becomes down-regulated in beta-cells soon after birth. Pancreata from CTGF null embryos have an increase in glucagon(+) cells with a concomitant decrease in insulin(+) cells, and show defects in islet morphogenesis. Loss of CTGF also results in a dramatic decrease in beta-cell proliferation at late gestation. Unlike CTGF null embryos, CTGF heterozygotes survive past birth and exhibit a range of islet phenotypes, including an intermingling of islet cell types, increased number of glucagon(+) cells, and beta-cell hypertrophy. (Molecular Endocrinology 23: 324-336, 2009)