Sloop K W, Meier B C, Bridwell J L, Parker G E, Schiller A M, Rhodes S J
Department of Biology, Indiana University-Purdue University Indianapolis 46202-5132, USA.
Mol Endocrinol. 1999 Dec;13(12):2212-25. doi: 10.1210/mend.13.12.0395.
Lhx3 is a LIM homeodomain transcription factor essential for pituitary development and motor neuron specification in mice. We identified two isoforms of human Lhx3, hLhx3a and hLhx3b, which differ in their ability to trans-activate pituitary gene targets. These factors are identical within the LIM domains and the homeodomain, but differ in their amino-terminal sequences preceding the LIM motifs. Both isoforms are localized to the nucleus and are expressed in the adult human pituitary, but gene activation studies demonstrate characteristic functional differences. Human Lhx3a trans-activated the alpha-glycoprotein subunit promoter and a reporter construct containing a high-affinity Lhx3 binding site more effectively than the hLhx3b isoform. In addition, hLhx3a synergized with the pituitary POU domain factor, Pit-1, to strongly induce transcription of the TSHbeta-subunit gene, while hLhx3b did not. We demonstrate that the differences in gene activation properties between hLhx3a and hLhx3b correlate with their DNA binding to sites within these genes. The short hLhx3b-specific amino-terminal domain inhibits DNA binding and gene activation functions of the molecule. These data suggest that isoforms of Lhx3 may play distinct roles during development of the mammalian pituitary gland and other neuroendocrine systems.
Lhx3是一种LIM同源结构域转录因子，对小鼠垂体发育和运动神经元特化至关重要。我们鉴定出了人类Lhx3的两种异构体，hLhx3a和hLhx3b，它们在反式激活垂体基因靶点的能力上存在差异。这些因子在LIM结构域和同源结构域内是相同的，但在LIM基序之前的氨基末端序列有所不同。两种异构体都定位于细胞核，且在成人垂体中表达，但基因激活研究显示出它们具有特征性的功能差异。与hLhx3b异构体相比，人类Lhx3a能更有效地反式激活α-糖蛋白亚基启动子以及含有高亲和力Lhx3结合位点的报告基因构建体。此外，hLhx3a与垂体POU结构域因子Pit-1协同作用，强烈诱导TSHβ亚基基因的转录，而hLhx3b则不能。我们证明，hLhx3a和hLhx3b在基因激活特性上的差异与它们与这些基因内位点的DNA结合有关。较短的hLhx3b特异性氨基末端结构域会抑制该分子的DNA结合和基因激活功能。这些数据表明，Lhx3的异构体可能在哺乳动物垂体腺和其他神经内分泌系统的发育过程中发挥不同的作用。
