Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signaling.
Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signaling.
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DOI：
10.1371/journal.pbio.1001218
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发表时间：
2011-12
期刊：
影响因子：
9.8
通讯作者：
Scholpp S
中科院分区：
文献类型：
--
作者：
Peukert D;Weber S;Lumsden A;Scholpp S
在原肠胚形成过程中，神经管开始轴向分化为前脑、中脑和后脑原基。在这个模式化阶段之后，大脑内部的进一步多样化被认为在不同的原基中基本上独立地进行。然而，在后期阶段维持大脑分区划分的机制却知之甚少。在前脑尾侧的前板中，有两个主要单位，丘脑和顶盖前区，每个单位都是一个发育区室。在这里，我们表明，适当的丘脑神经元分化需要Lhx 2和Lhx 9功能。在Lhx 2/Lhx 9缺陷的斑马鱼胚胎中，分化过程被阻断，背侧相邻的Wnt阳性上丘脑扩展到丘脑。这导致尾侧前脑中Wnt信号传导的上调。Lhx 2/Lhx 9功能的缺乏以及Wnt信号的增加改变了丘脑特异性细胞粘附因子pcdh 10 b的表达，并导致随后的尾侧前脑的显著前后紊乱。因此，我们认为，在最初的神经管图案，神经发生在脑室内的影响的完整性的神经元祖细胞池和边界形成的神经节隔室。丘脑是身体和大脑之间的界面。它将感觉器官与高级大脑区域连接起来，并调节睡眠，警觉和意识等过程。我们对这个中央中继站的萌芽发展的了解仍然是支离破碎的。在这里，我们表明，转录因子Lhx 2和Lhx 9是必不可少的中继丘脑的发展。缺乏Lhx 2/Lhx 9的斑马鱼胚胎具有停滞的神经发生-神经元祖细胞积累但不完成其向丘脑神经元的分化。此外，我们发现邻近的表达Wnt的上丘脑扩展到这些胚胎中包含错误指定的丘脑的空间。我们确定了丘脑特异性细胞粘附调节剂，Pcdh 10 b，这是由经典的Wnt信号控制。Lhx 2/Lhx 9缺陷胚胎中Wnt依赖性Pcdh 10 b功能的改变导致丘脑和相邻脑室的混合，因此尾前脑内的区域化丢失。发育中的中枢神经系统组织成分子上不同但短暂的片段，区域分化的影响在发育中的后脑中已经得到了很好的证实。我们的结论是，这也适用于尾部前脑：Lhx 2和Lhx 9出现作为驱动神经发生和维持区域完整性的尾部前脑的关键因素。这是大脑中这个重要中继站形成的两个先决条件。
Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment. The thalamus is the interface between the body and the brain. It connects sensory organs with higher brain areas and modulates processes such as sleep, alertness, and consciousness. Our knowledge about the embryonic development of this central relay station is still fragmented. Here, we show that the transcription factors Lhx2 and Lhx9 are essential for the development of the relay thalamus. Zebrafish embryos lacking Lhx2/Lhx9 have stalled neurogenesis - neuronal progenitor cells accumulate but do not complete their differentiation into thalamic neurons. In addition, we find that the neighboring Wnt-expressing epithalamus expands into the space containing mis-specified thalamus in these embryos. We identified a thalamus-specific cell adhesion modulator, Pcdh10b, which is controlled by canonical Wnt signaling. Altered Wnt-dependent Pcdh10b function in Lhx2/Lhx9-deficient embryos leads to intermingling of the thalamus and adjacent brain compartments and consequently regionalization within the caudal forebrain is lost. Organization of the developing CNS into molecularly distinct but transient segments and the implications for regional differentiation are well established for the developing hindbrain. We conclude that this applies to caudal forebrain too: Lhx2 and Lhx9 emerge as crucial factors driving neurogenesis and maintaining the regional integrity of the caudal forebrain. These are two prerequisites for the formation of this important relay station in the brain.
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