Functional analysis of Rfx6 and mutant variants associated with neonatal diabetes

被引:27
作者
Pearl, Esther J. [1 ,2 ,3 ]
Jarikji, Zeina [1 ]
Horb, Marko E. [1 ,2 ,3 ,4 ,5 ]
机构
[1] Inst Rech Clin Montreal, Lab Mol Organogenesis, Montreal, PQ H2V 4K1, Canada
[2] Univ Montreal, Dept Med, Montreal, PQ H3T 3J7, Canada
[3] Ctr Hosp Univ Montreal, Ctr Rech, Montreal Diabet Res Ctr, Montreal, PQ H1W 4A4, Canada
[4] McGill Univ, Div Expt Med, Montreal, PQ H3A 2B2, Canada
[5] McGill Univ, Dept Anat & Cell Biol, Montreal, PQ H3A 2B2, Canada
基金
美国国家卫生研究院;
关键词
Rfx6; Pancreas development; Neonatal diabetes; Mitchell-Riley; Organogenesis; Xenopus; TRANSCRIPTION FACTOR RFX3; WOLCOTT-RALLISON-SYNDROME; GENE-EXPRESSION; HISTONE H1T; GLUCOKINASE DEFICIENCY; CELL-DIFFERENTIATION; ACTIVATING MUTATIONS; REGULATORY FACTOR; KIR6.2; KCNJ11; INSULIN GENE;
D O I
10.1016/j.ydbio.2010.12.043
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
Mutations in rfx6 were recently associated with Mitchell-Riley syndrome, which involves neonatal diabetes, and other digestive system defects. To better define the function of Rfx6 in early endoderm development we cloned the Xenopus homologue. Expression of rfx6 begins early, showing broad expression throughout the anterior endoderm; at later stages rfx6 expression becomes restricted to the endocrine cells of the gut and pancreas. Morpholino knockdown of rfx6 caused a loss of pancreas marker expression, as well as other abnormalities. Co-injection of exogenous wild-type rfx6 rescued the morpholino phenotype in Xenopus tadpoles, whereas attempts to rescue the loss-of-function phenotype using mutant rfx6 based on Mitchell-Riley patients were unsuccessful. To better define the pleiotropic effects, we performed microarray analyses of gene expression in knockdown foregut tissue. In addition to pancreatic defects, the microarray analyses revealed downregulation of lung, stomach and heart markers and an upregulation of kidney markers. We verified these results using RT-PCR and in situ hybridization. Based on the different rfx6 expression patterns and our functional analyses, we propose that rfx6 has both early and late functions. In early development Rfx6 plays a broad role, being essential for development of most anterior endodermal organs. At later stages however, Rfx6 function is restricted to endocrine cells. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:135 / 145
页数:11
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