Review of the neuroanatomic landscape implicated in glucose sensing and regulation of nutrient signaling: immunophenotypic localization of diabetes gene Tcf7l2 in the developing murine brain.
Review of the neuroanatomic landscape implicated in glucose sensing and regulation of nutrient signaling: immunophenotypic localization of diabetes gene Tcf7l2 in the developing murine brain.
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DOI：
10.1016/j.jchemneu.2012.06.002
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发表时间：
2012-10
影响因子：
2.8
通讯作者：
Hall J
中科院分区：
文献类型：
--
作者：
Weaver C;Turner N;Hall J
已发现转录因子7样2（Tcf 7 l2）基因中的遗传变异赋予2型糖尿病和减弱胰岛素分泌的显著风险。基于其基因组广泛相关性，Tcf 7 l2被认为是迄今为止糖尿病的单一最重要的预测因子。以前的研究表明，Tcf 7 l2 mRNA在成年人大脑中的定位Tcf 7 l2在中枢神经系统的能量稳态调节中的假定作用。本研究进一步表征了Tcf 7 l2后代在E12.5和P1之间的发育时间段期间脑中肽表达的免疫表型分布。Tcf 7 l2 −/−在P1之后是致命的。结果表明，虽然在Tcf 7 l2 −/−小鼠发育中的大脑中发现了可忽略的TCF 7 L2表达，但TCF 7 L2蛋白在E18.5时在大脑中相对广泛和稳健地表达，并在Tcf 7 l2 +/-和Tcf 7 l2 +/+后代的神经元群体和大脑区域中表现出特异性表达。强烈的免疫表型标记被发现在间脑结构的丘脑，这表明Tcf 7 L2在丘脑活动的发展和维护中的作用。强烈表达的TCF 7 L2定位于选择下丘脑和视前核，表明TCF 7 L2在控制能量平衡的神经元内的功能。脑干和室周器官核内TCF 7 L2的连续神经元染色扩展了TCF 7 L2在自主神经元内的定位及其与自主功能的潜在整合。此外，在上级和下丘的顶盖和被盖结构中发现了强大的TCF 7 L2表达，以及在E16和E18.5的大脑和海马皮质的神经上皮中的瞬时表达。TCF 7 L2肽定位的模式相比，成人蛋白质合成的化学/解剖景观的葡萄糖传感表现出良好的相关性之间的配合，其表达和区域，核，和途径调节能量稳态通过整合和响应外周内分泌，代谢和神经元信号。还发现TCF与调节能量稳态的肽（包括AgRP、POMC和NPY）共定位。TCF 712的一些变体已显示损害GLP-1诱导的胰岛素分泌，也发现其与GLP-1在成年TCF野生型后代中共定位。受损的Tcf 7 l2介导的神经调节可能有助于2型糖尿病的风险和/或潜在的病理生理学，这在Tcf 7 l2变体的基因组研究中发现了高表达。
Genetic variants in the transcription factor 7-like 2(Tcf7l2) gene have been found to confer a significant risk of type 2 diabetes and attenuated insulin secretion. Based on its genomic wide association Tcf7l2 is considered the single most important predictor of diabetes to date. Previous studies of Tcf7l2 mRNA localization in the adult brain suggest a putative role of Tcf7l2 in the CNS regulation of energy homeostasis. The present study further characterizes the immunophenotypic distribution of peptide expression in the brains of Tcf7l2 progeny during developmental time periods between E12.5 and P1. Tcf7l2 −/− is lethal beyond P1. Results show that while negligible TCF7L2 expression is found in the developing brains of Tcf7l2−/−mice, TCF7L2 protein is relatively widespread and robustly expressed in the brain by E18.5 and exhibits specific expression within neuronal populations and regions of the brain in Tcf7l2+/- and Tcf7l2+/+ progeny. Strong immunophenotypic labeling was found in the diencephalic structure of the thalamus that suggests a role of Tcf7l2 in the development and maintenance of thalamic activity. Strongly expressed TCF7L2 was localized in select hypothalamic and preoptic nuclei indicative of Tcf7l2 function within neurons controlling energy balance. Definitive neuronal staining for TCF7L2 within nuclei of the brain stem and circumventricular organs extends TCF7L2 localization within autonomic neurons and its potential integration with autonomic function. In addition robust TCF7L2 expression was found in the tectal and tegmental structures of the superior and inferior colliculi as well as transient expression in neuroepithelium of the cerebral and hippocampal cortices of E16 and E18.5. Patterns of TCF7L2 peptide localization when compared to the adult protein synthetic chemical/anatomical landscape of glucose sensing exhibit a good correlational fit between its expression and regions, nuclei, and pathways regulating energy homeostasis via integration and response to peripheral endocrine, metabolic and neuronal signaling. TCF was also found co-localized with peptides that regulate energy homeostasis including AgRP, POMC and NPY. TCF7l2, some variants of which have been shown to impair GLP-1-induced insulin secretion, was also found co-localize with GLP-1 in adult TCF wild type progeny. Impaired Tcf7l2-mediated neural regulation may contribute to the risk and/or underlying pathophysiology of type 2 diabetes that has found high expression in genomic studies of Tcf7l2 variants.
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DOI：
10.1152/ajpregu.2001.280.2.r563
发表时间：
2001-02-01
影响因子：
2.8
作者：
Beverly, JL;De Vries, MG;Arseneau, LM
通讯作者：
Arseneau, LM
影响因子：
3.5
作者：
BONDY, CA;LEE, WH;ZHOU, J
通讯作者：
ZHOU, J
影响因子：
12.7
作者：
AUER, RN;WIELOCH, T;SIESJO, BK
通讯作者：
SIESJO, BK
影响因子：
4.7
作者：
Boado, RJ;Pardridge, WM
通讯作者：
Pardridge, WM
影响因子：
2.9
作者：
Cates, PS;O'Byrne, KT
通讯作者：
O'Byrne, KT