RET(Men2B)-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1(-/-) mice.
RET(Men2B)-transgene produces sympathoadrenal tumors but does not prevent intestinal aganglionosis in gdnf-/- or gfr alpha-1(-/-) mice.
复制标题
RET(Men2B)-转基因产生交感肾上腺肿瘤，但不能预防 gdnf-/- 或 gfr alpha-1(-/-) 小鼠的肠无神经节细胞病。
DOI：
10.1007/s10024001-0039-9
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Kapur,RP
中科院分区：
文献类型：
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作者：
Rajan,I;Gestblom,C;Kapur,RP
多发性内分泌肿瘤2B型（MEN 2B）综合征是由RET基因的错义突变引起的，该基因在蛋白质的细胞内激酶结构域中将Met 918替换为Thr。这种单一氨基酸取代将受体转化为组成性活性单体激酶（RETMen 2B），并产生常染色体显性遗传综合征，其特征为甲状腺髓样癌、嗜铬细胞瘤、肌肉骨骼异常和粘膜神经节细胞瘤。配体GDNF通过辅助受体GFRα-1刺激RET活性。体外研究表明，GDNF/GFRα-1刺激增强了RETMen 2B的激酶和促有丝分裂特性。一个相关的临床问题是GDNF或GFRα-1的消融是否可以改变MEN 2B综合征的发病率或严重程度。我们报道了在小鼠中由RETMen 2B转基因引起的神经节细胞瘤肿瘤不受gdnf或gfrα-1缺失的影响。inret，gdnf，orgfrα-1功能缺失突变导致小鼠全肠无神经节细胞症。我们发现，在肠神经祖细胞定居肠道后，RETMen 2B转基因在肠神经祖细胞中的表达不能预防与gdnf或gfrα-1缺乏相关的肠神经节细胞减少症。
Multiple endocrine neoplasia type 2B (MEN2B) syndrome is caused by a missense mutation in theRETgene, which replaces Met918 by Thr in the intracellular kinase domain of the protein. This single amino acid substitution transforms the receptor into a constitutively active monomeric kinase (RETMen2B) and produces an autosomal dominant syndrome characterized by medullary thyroid carcinoma, pheochromocytomas, musculoskeletal anomalies, and mucosal ganglioneuromas. The ligand, GDNF, stimulates RET activity through a co-receptor, GFRα-1. In vitro studies have shown that the kinase and mitogenic properties of RETMen2Bare enhanced by GDNF/GFRα-1 stimulation. A relevant clinical question is whether ablation of either GDNF or GFRα-1 could alter penetrance or severity of the MEN2B syndrome. We report that ganglioneuromatous tumors caused by a RETMen2Btransgene in mice are not affected grossly or microscopically by the absence of gdnf or gfrα-1. Loss-of-function mutations inret, gdnf, orgfrα-1cause pan-intestinal aganglionosis in mice. We find that expression of the RETMen2Btransgene in enteric neural progenitors, after they colonize the gut, does not prevent intestinal aganglionosis associated with gdnf or gfrα-1 deficiency.