Making a mes: A transcription factor-microRNA pair governs the size of the midbrain and the dopaminergic progenitor pool.
Making a mes: A transcription factor-microRNA pair governs the size of the midbrain and the dopaminergic progenitor pool.
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DOI：
10.1080/23262133.2014.998101
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发表时间：
2015-01-01
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影响因子：
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通讯作者：
Awatramani, Rajeshwar
中科院分区：
文献类型：
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作者：
Anderegg, Angela;Awatramani, Rajeshwar
典型的Wnt信号对于中脑多巴胺能祖细胞的规范、增殖和神经发生至关重要。然而，控制Wnt信号的机制仍有待充分阐明。Wnt1是胚胎中脑的一个关键配体，并指导增殖、存活、分化和神经发生。在最近的一项研究中，我们发现转录因子Lmx1b促进Wnt1/Wnt信号传导和多巴胺能祖细胞扩增，与早期研究一致。此外，Lmx1b驱动一种称为Rmst的非编码RNA的表达，Rmst在其最后一个内含子中含有miR135a2。miR135a2反过来靶向Lmx1b以及几个Wnt通路靶点。miR135a2在中脑的条件性过表达，特别是在早期，导致多巴胺能祖细胞池减少，多巴胺能神经元减少，与Wnt信号传导减少一致。我们提出了一个Lmx1b和miR135a2影响Wnt1和Wnt信号水平以及多巴胺能祖细胞库扩张的模型。进一步的功能丧失实验和目标的生化验证将是验证该模型的关键。Wnt激动剂最近被用于体外编程干细胞向多巴胺能的命运，突出了调节Wnt途径的药物的重要性。
Canonical Wnt signaling is critical for midbrain dopaminergic progenitor specification, proliferation, and neurogenesis. Yet mechanisms that control Wnt signaling remain to be fully elucidated. Wnt1 is a key ligand in the embryonic midbrain, and directs proliferation, survival, specification and neurogenesis. In a recent study, we reveal that the transcription factor Lmx1b promotes Wnt1/Wnt signaling, and dopaminergic progenitor expansion, consistent with earlier studies. Additionally, Lmx1b drives expression of a non-coding RNA called Rmst, which harbors miR135a2 in its last intron. miR135a2 in turn targets Lmx1b as well as several Wnt pathway targets. Conditional overexpression of miR135a2 in the midbrain, particularly during an early time, results in a decreased dopaminergic progenitor pool, and less dopaminergic neurons, consistent with decreased Wnt signaling. We propose a model in which Lmx1b and miR135a2 influence levels of Wnt1 and Wnt signaling, and expansion of the dopaminergic progenitor pool. Further loss of function experiments and biochemical validation of targets will be critical to verify this model. Wnt agonists have recently been utilized for programming stem cells toward a dopaminergic fate in vitro, highlighting the importance of agents that modulate the Wnt pathway.