Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex.
Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex.
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DOI：
10.1523/jneurosci.2303-09.2009
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发表时间：
2009-09-09
期刊：
影响因子：
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通讯作者：
Johnson JE
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文献类型：
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作者：
Meredith DM;Masui T;Swift GH;MacDonald RJ;Johnson JE
Ptf 1a与E蛋白和Rbpj一起沿着形成转录因子复合物PTF 1-J，其对于脊髓、视网膜和小脑中的抑制性神经元的适当特化是必需的。在这里，我们表明，两个高度保守的非编码基因组区域，远端2.3 kb的序列位于13.4 kb的5′和12.4 kb的序列位于直接3′的Ptf 1a编码区，在控制Ptf 1a在所有这些域的表达具有不同的活性。5′ 2.3 kb序列作为一个自动调节元件，指导报告基因表达到发育中的神经系统中的所有Ptf 1a结构域。通过PTF 1-J复合物在体外的结合，Ptf 1a在体内定位于该基因组区域，以及Ptf 1a在转基因小鼠中对调节元件活性的体内要求，证明了该元件的自身调节活性。与此相反，12.4 kb的3′调控区不含任何保守的PTF 1位点，其在转基因小鼠中的表达不依赖于Ptf 1a。因此，在发育中的神经系统中启动Ptf 1a表达的调控信息位于Ptf 1a基因的12.4 kb序列3′内。总之，这些结果确定了多种转录机制，控制Ptf 1a的水平，一个通过PTF 1-J复合物的自动调节调节水平，和其他Ptf 1a的初始激活的独立机制。
Ptf1a, along with an E protein and Rbpj, forms the transcription factor complex PTF1-J that is essential for proper specification of inhibitory neurons in the spinal cord, retina, and cerebellum. Here we show that two highly conserved non-coding genomic regions, a distal 2.3 kb sequence located 13.4 kb 5′ and a 12.4 kb sequence located immediately 3′ of the Ptf1a coding region, have distinct activity in controlling Ptf1a expression in all of these domains. The 5′ 2.3 kb sequence functions as an autoregulatory element and directs reporter gene expression to all Ptf1a domains in the developing nervous system. The autoregulatory activity of this element was demonstrated by binding of the PTF1-J complex in vitro, Ptf1a localization to this genomic region in vivo, and the in vivo requirement of Ptf1a for the activity of the regulatory element in transgenic mice. In contrast, the 12.4 kb 3′ regulatory region does not contain any conserved PTF1 sites, and its expression in transgenic mice is independent of Ptf1a. Thus, regulatory information for initiation of Ptf1a expression in the developing nervous system is located within the 12.4 kb sequence 3′ of the Ptf1a gene. Together, these results identify multiple transcriptional mechanisms that control Ptf1a levels, one modulating levels by autoregulation through the PTF1-J complex, and the other a Ptf1a-independent mechanism for initial activation.