Transcription factor expression in the developing human fetal endocrine pancreas
Transcription factor expression in the developing human fetal endocrine pancreas
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DOI：
10.1007/s00125-008-1006-z
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发表时间：
2008-07-01
期刊：
影响因子：
8.2
通讯作者：
Wang, R.
中科院分区：
文献类型：
--
作者：
Lyttle, B. M.;Krishnamurthy, J. Li M.;Wang, R.
目的/假设在啮齿动物系统中，胰腺内分泌细胞分化过程中发生的形态学变化已被证明依赖于转录因子表达的顺序改变。然而，人类的类似数据有限。本研究的目的是提供人胚胎发育过程中胰腺形态、转录因子基因表达和蛋白定位之间的联系。（胎龄8-12周），中期（14-16周）和晚期（19-21周）阶段，使用免疫组织学，结果胰腺十二指肠同源框1（PDX-1）（+）/细胞角蛋白19（+）细胞在正常对照组显著减少，（p < 0.001），同时PDX-1（+）/胰岛素（+）细胞从8周至21周增加（p < 0.05）。注意到胰岛簇内的PDX-1/胰岛素共定位增加，而未发现PDX-1与胰高血糖素的共表达，表明PDX-1的缺失对于α细胞形成是必需的。鉴于神经生成素3（NGN 3）表达对于在啮齿动物胰腺中建立内分泌细胞程序至关重要，我们检查了其在PDX-1（+）、胰岛素（+）和胰高血糖素（+）细胞中的表达模式和共定位。在早期发育期间注意到NGN 3与PDX-1、胰岛素和胰高血糖素的共定位，在中期和晚期显著降低（p < 0.001）。我们对与NGN 3相关的转录因子的微阵列和共定位分析表明，ISL 1转录因子（ISL 1）、神经源性分化1（NEUROD 1）、NK 2相关转录因子相关基因座2（NKX 2 -2）和配对盒基因6（PAX 6）在发育过程中上调，并存在于所有四种内分泌细胞类型中，而NK 6相关转录因子相关基因座2（NKX 2 -2）和配对盒基因6（PAX 6）在发育过程中上调，基因座1（NKX 6 -1）仅在β细胞中表达。结论/解释本研究是确定参与人胎儿内分泌胰腺发育的关键分子因子的重要一步。
Aims/hypothesis Morphological changes that occur during pancreatic endocrine cell differentiation have been shown in rodent systems to be dependent on sequential alterations in transcription factor expression. However, similar data for humans have been limited. The aim of the present study was to provide a connection between pancreatic morphology, transcription factor gene expression and protein localisation during human fetal development.Methods Human fetal pancreases were examined at early (8-12 weeks of fetal age), middle (14-16 weeks) and late (19-21 weeks) stages, using immunohistological, microarray and qRT-PCR analyses.Results We observed a significant decrease in pancreatic duodenal homeobox 1 (PDX-1)(+)/cytokeratin 19(+) cells (p < 0.001), with a simultaneous increase in PDX-1(+)/insulin(+) cells from 8 to 21 weeks (p < 0.05). Increased PDX-1/insulin co-localisation within islet clusters was noted, while no co-expression of PDX-1 with glucagon was found, suggesting that loss of PDX-1 is essential for alpha cell formation. Given that neurogenin 3 (NGN3) expression is critical for establishing the endocrine cell programme in the rodent pancreas, we examined its expression pattern and co-localisation in PDX-1(+), insulin(+) and glucagon(+) cells. Co-localisation of NGN3 with PDX-1, insulin and glucagon was noted during early development, with significant decreases in middle and late stages (p < 0.001). Our microarray and co-localisation analyses of transcription factors linked to NGN3 demonstrated that ISL1 transcription factor (ISL1), neurogenic differentiation 1 (NEUROD1), NK2 related transcription factor related, locus 2 (NKX2-2) and paired box gene 6 (PAX6) were upregulated during development and present in all four endocrine cell types, while NK6 related transcription factor related, locus 1 (NKX6-1) was expressed exclusively in beta cells.Conclusions/interpretation This study is an important step towards identifying key molecular factors involved in development of the human fetal endocrine pancreas.