Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation.,Nature Communications

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Transcriptional repression of Plxnc1 by Lmx1a and Lmx1b directs topographic dopaminergic circuit formation.
Nature Communications ( IF 14.7 ) Pub Date : 2017-10-16 , DOI: 10.1038/s41467-017-01042-0
Audrey Chabrat _{1,

2} , Guillaume Brisson _{1,

2} , Hélène Doucet-Beaupré _{1,

2} , Charleen Salesse _{1,

2} , Marcos Schaan Profes _{1,

2} , Axelle Dovonou _{1,

2} , Cléophace Akitegetse _{1,

2} , Julien Charest _{1,

2} , Suzanne Lemstra ₃ , Daniel Côté _{2,

4} , R Jeroen Pasterkamp ₃ , Monica I Abrudan _{5,

6} , Emmanouil Metzakopian ₅ , Siew-Lan Ang ₇ , Martin Lévesque _{1,

2}

Affiliation

Mesodiencephalic dopamine neurons play central roles in the regulation of a wide range of brain functions, including voluntary movement and behavioral processes. These functions are served by distinct subtypes of mesodiencephalic dopamine neurons located in the substantia nigra pars compacta and the ventral tegmental area, which form the nigrostriatal, mesolimbic, and mesocortical pathways. Until now, mechanisms involved in dopaminergic circuit formation remained largely unknown. Here, we show that Lmx1a, Lmx1b, and Otx2 transcription factors control subtype-specific mesodiencephalic dopamine neurons and their appropriate axon innervation. Our results revealed that the expression of Plxnc1, an axon guidance receptor, is repressed by Lmx1a/b and enhanced by Otx2. We also found that Sema7a/Plxnc1 interactions are responsible for the segregation of nigrostriatal and mesolimbic dopaminergic pathways. These findings identify Lmx1a/b, Otx2, and Plxnc1 as determinants of dopaminergic circuit formation and should assist in engineering mesodiencephalic dopamine neurons capable of regenerating appropriate connections for cell therapy.Midbrain dopaminergic neurons (mDAs) in the VTA and SNpc project to different regions and form distinct circuits. Here the authors show that transcription factors Lmx1a, Lmx1b, and Otx2 control the axon guidance of mDAs and the segregation of mesolimbic and nigrostriatal dopaminergic pathways.

中文翻译：

Lmx1a 和 Lmx1b 对 Plxnc1 的转录抑制指导拓扑多巴胺能回路的形成。

中间脑多巴胺神经元在调节多种大脑功能（包括随意运动和行为过程）中发挥着核心作用。这些功能由位于黑质致密部和腹侧被盖区的中间脑多巴胺神经元的不同亚型提供，这些神经元形成黑质纹状体、中脑边缘和中皮质通路。到目前为止，参与多巴胺能回路形成的机制仍然很大程度上未知。在这里，我们证明 Lmx1a、Lmx1b 和 Otx2 转录因子控制亚型特异性中间脑多巴胺神经元及其适当的轴突神经支配。我们的结果表明，轴突引导受体 Plxnc1 的表达被 Lmx1a/b 抑制，并被 Otx2 增强。我们还发现 Sema7a/Plxnc1 相互作用负责黑质纹状体和中脑边缘多巴胺能通路的分离。这些发现将 Lmx1a/b、Otx2 和 Plxnc1 确定为多巴胺能回路形成的决定因素，应有助于设计能够再生适当连接以进行细胞治疗的中脑多巴胺神经元。VTA 和 SNpc 中的中脑多巴胺能神经元 (mDA) 投射到不同区域和形成不同的电路。作者在此表明转录因子 Lmx1a、Lmx1b 和 Otx2 控制 mDA 的轴突引导以及中脑边缘和黑质纹状体多巴胺能通路的分离。

更新日期：2017-10-16

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