Distinct regulatory elements mediate the dynamic expression pattern of Nkx3.1
Distinct regulatory elements mediate the dynamic expression pattern of Nkx3.1
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DOI：
10.1002/dvdy.20596
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发表时间：
2005-12-01
影响因子：
2.5
通讯作者：
Bieberich, CJ
中科院分区：
文献类型：
--
作者：
Chen, H;Mutton, LN;Bieberich, CJ
小鼠中Nkx3.1功能的丧失导致前列腺发育和上皮增生的缺陷，表明该基因在前列腺分化的启动和维持中起重要作用。在人类中，NKX3.1表达降低与前列腺癌的进展相关。尽管在前列腺发育和疾病中有这些作用，但Nkx3.1的转录调控尚未得到系统的解决。在转基因小鼠的报告基因的方法被用来确定调控区，决定Nkx3.1的表达模式。已经鉴定出来自Nkx3.1基因座的32 kb DNA片段，该片段指定了胚胎发生和产后生命期间的预期表达模式。缺失分析表明，在不同位点介导表达的顺式调控元件是可分离的。Nkx3.1编码区下游的5 kb片段含有支持前列腺和尿道球腺表达的元件，而上游片段含有指导体节和睾丸表达的元件。报告基因表达分析还揭示了Nkx3.1在男性中表达的几个先前未知的位点，包括尿道腺、尿道憩室中的腺细胞和前列腺中的基底上皮细胞。此外，这些分析揭示了Nkx3.1在女性尿道腺中的表达。Nkx3.1顺式调节元件的鉴定为解剖参与前列腺器官发生和发病机制的信号传导通路提供了一个独特的起点，并提供了一个在整个前列腺发育过程中干扰基因表达的系统。
Loss of Nkx3.1 function in mice results in defects in prostate development and epithelial hyperplasia, indicating that this gene plays important roles in both the initiation and maintenance of prostate differentiation. In humans, decreased NKX3.1 expression is associated with the progression of prostate cancer. Despite these roles in prostate development and disease, the transcriptional regulation of Nkx3.1 has not been systematically addressed. A reporter gene approach in transgenic mice was used to identify regulatory regions that dictate the expression pattern of Nkx3.1. A 32-kb DNA fragment from the Nkx3.1 locus that specifies the expected expression pattern during embryogenesis and postnatal life has been identified. Deletion analyses demonstrated that cis-regulatory elements that mediate expression in distinct sites are separable. A 5-kb fragment downstream of the Nkx3.1 coding region contains elements that support expression in the prostate and bulbourethral glands, whereas an upstream fragment contains elements that direct expression in somites and testes. Reporter gene expression analyses also revealed several previously unknown sites of Nkx3.1 expression in males, including urethral glands, glandular cells in the urethral diverticulum and basal epithelial cells in the prostate. In addition, these analyses revealed Nkx3.1 expression in female urethral glands. The identification of Nkx3.1 cis-regulatory elements provides a unique starting point to dissect signaling pathways involved in prostate organogenesis and pathogenesis and provides a system to perturb gene expression throughout prostate development.