Perturbation of hoxb5 signaling in vagal neural crests down-regulates Ret leading to intestinal hypoganglionosis in mice

被引:45
|
作者
Lui, Vincent C. H. [1 ]
Cheng, William W. C. [1 ]
Leon, Thomas Y. Y. [1 ]
Lau, Danny K. C. [1 ]
Garcia-Bareclo, Maria-Mercedes [1 ]
Miao, Xiao P. [1 ]
Kam, Mandy K. M. [1 ]
So, Man T. [1 ]
Chen, Yan [1 ]
Wall, Nancy A. [2 ]
Sham, Mai H. [3 ]
Tam, Paul K. H. [1 ,4 ]
机构
[1] Univ Hong Kong, Dept Surg, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China
[2] Lawrence Univ, Dept Biol, Appleton, WI 54912 USA
[3] Univ Hong Kong, Dept Biochem, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China
[4] Univ Hong Kong, Genome Res Ctr, LKS Fac Med, Hong Kong, Hong Kong, Peoples R China
关键词
D O I
10.1053/j.gastro.2008.01.028
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: The enteric nervous system (ENS) controls intestinal peristalsis, and defective development of this system results in hypo/aganglionosis, as seen in Hirschsprung's disease. In the embryo, vagal neural crest cells (NCC) migrate and colonize the intestine rostrocaudally then differentiate into the ganglia of the ENS. Vagal NCC express the homeobox gene HoxbS, a transcriptional activator, in human and mouse, so we used transgenic mice to investigate the function of Hoxb5 and the receptor tyrosine kinase gene Ret, which is affected in many patients with Hirschsprung's disease, in ENS development. Methods: We perturbed the HoxbS pathway by expressing a chimeric protein enb5, in which the transcription activation domain of Hoxb5 was replaced with the repressor domain of the Drosophila engrailed protein (en), in vagal NCC. This enb5 transcriptional repressor competes with wild-type Hoxb5 for binding to target genes, exerting a dominant negative effect. Results: We observed that 30.6% +/- 2.3% of NCC expressed enb5 and that these enb5-expressing NCC failed to migrate to the distal intestine. A 34%-37% reduction of ganglia (hypoganglionosis) and slow peristalsis and, occasionally, absence of ganglia and intestinal obstruction were observed in enb5-expressing mice. Ret expression was markedly reduced or absent in NCC and ganglia, and enb5 blocked Hoxb5 induction of Ret in neuroblastoma cells. Conclusions: our data indicate that Ret is a downstream target of Hoxb5 whose perturbation causes Ret haploinsufficiency, impaired NCC migration, and hypo/aganglionosis, suggesting that Hoxb5 may contribute to the etiology of Hirschsprung's disease.
引用
收藏
页码:1104 / 1115
页数:12
相关论文
共 5 条
  • [1] Perturbation of hoxb5 signaling in vagal neural crests down-regulates ret leading to intestinal hypoganglionosis in mice (vol 134, pg 1104, 2008)
    Lui, V. C. H.
    Cheng, W. W. C.
    Leon, T. Y. Y.
    [J]. GASTROENTEROLOGY, 2008, 135 (02) : 713 - 713
  • [2] Perturbation of Hoxb5 signaling in vagal and trunk neural crest cells causes apoptosis and neurocristopathies in mice
    Kam, M. K. M.
    Cheung, M. C. H.
    Zhu, J. J.
    Cheng, W. W. C.
    Sat, E. W. Y.
    Tam, P. K. H.
    Lui, V. C. H.
    [J]. CELL DEATH AND DIFFERENTIATION, 2014, 21 (02): : 278 - 289
  • [3] Perturbation of Hoxb5 signaling in vagal and trunk neural crest cells causes apoptosis and neurocristopathies in mice
    M K M Kam
    M C H Cheung
    J J Zhu
    W W C Cheng
    E W Y Sat
    P K H Tam
    V C H Lui
    [J]. Cell Death & Differentiation, 2014, 21 : 278 - 289
  • [4] Perturbation of Hoxb5 signalling in vagal neural crest cells causes defective development of the enteric nervous system
    Lui, V. C. H.
    Cheng, W. W. C.
    Chen, Y.
    Sham, M. H.
    Tam, P. K. H.
    [J]. MECHANISMS OF DEVELOPMENT, 2005, 122 : S93 - S93
  • [5] Lymphotoxin β signaling down-regulates cycleoxygenase-2 expression in mice and the intestinal cell line HT-29
    Tessner, TG
    Riehl, TE
    Stenson, WF
    [J]. GASTROENTEROLOGY, 2002, 122 (04) : A83 - A83