Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C-elegans
Cis-regulatory mechanisms of left/right asymmetric neuron-subtype specification in C-elegans
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DOI：
10.1242/dev.030064
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发表时间：
2009-01-01
期刊：
影响因子：
4.6
通讯作者：
Hobert, Oliver
中科院分区：
文献类型：
--
作者：
Etchberger, John F.;Flowers, Eileen B.;Hobert, Oliver
解剖学和功能上定义的神经元类型有时会根据独特的功能或分子特性进一步分类为单个亚型。为了更好地理解控制神经元类型规范的发育程序与控制神经元亚型规范的程序之间的机制联系，我们分析了秀丽隐杆线虫神经系统中发生在左/右轴上的神经元亚型规范程序。终端选择转录因子CHE-1是ASE神经元类别分化所必需的，转录因子和mirna的基因调控反馈回路是将两种ASE神经元分化为不对称的左右亚型（ASEL和ASER）所必需的。然而，che -1依赖性ASE神经元类别规范与随后的左-右亚型规范程序之间的联系尚不清楚。我们在这里表明，CHE-1在控制双边对称ASE神经元类别规范和随后的左右亚型规范程序方面具有遗传可分的功能。神经元类别规范和非对称亚类规范都依赖于对称和非对称表达靶基因中的che -1结合位点（“ASE基序”），但在非对称表达靶基因的情况下，ASE基序的活性是通过一系列额外的顺式调控元件来调节的。根据靶基因的不同，这些顺式调控元件可促进或抑制CHE-1的活性。这些L/R不对称顺式调控元件的活性由che-1本身间接控制，揭示了一个前馈环结构，其中che-1限制其自身的活性。CHE-1与ASE基序的相对结合亲和力也取决于基因是双边表达还是以左/右不对称方式表达。我们的分析提供了对神经元亚型规范的分子机制的见解，表明神经元类型特异性选择基因的活性是通过各种不同的手段来调节的，从而使单个神经元类别多样化为特定的亚类。它还表明，前馈回路基序可能是神经元多样化事件的一个突出特征。
Anatomically and functionally defined neuron types are sometimes further classified into individual subtypes based on unique functional or molecular properties. To better understand how developmental programs controlling neuron type specification are mechanistically linked to programs controlling neuronal subtype specification, we have analyzed a neuronal subtype specification program that occurs across the left/right axis in the nervous system of the nematode C. elegans. A terminal selector transcription factor, CHE-1, is required for the specification of the ASE neuron class, and a gene regulatory feedback loop of transcription factors and miRNAs is required to diversify the two ASE neurons into an asymmetric left and right subtype (ASEL and ASER). However, the link between the CHE-1-dependent ASE neuron class specification and the ensuing left-right subtype specification program is poorly understood. We show here that CHE-1 has genetically separable functions in controlling bilaterally symmetric ASE neuron class specification and the ensuing left-right subtype specification program. Both neuron class specification and asymmetric subclass specification depend on CHE-1-binding sites ('ASE motifs') in symmetrically and asymmetrically expressed target genes, but in the case of asymmetrically expressed target genes, the activity of the ASE motif is modulated through a diverse set of additional cis-regulatory elements. Depending on the target gene, these cis-regulatory elements either promote or inhibit the activity of CHE-1. The activity of these L/R asymmetric cis-regulatory elements is indirectly controlled by che-1 itself, revealing a feed-forward loop configuration in which che-1 restricts its own activity. Relative binding affinity of CHE-1 to ASE motifs also depends on whether a gene is expressed bilaterally or in a left/right asymmetric manner. Our analysis provides insights into the molecular mechanisms of neuronal subtype specification, demonstrating that the activity of a neuron type-specific selector gene is modulated by a variety of distinct means to diversify individual neuron classes into specific subclasses. It also suggests that feed-forward loop motifs may be a prominent feature of neuronal diversification events.