Subtype specification of GABAergic amacrine cells by the orphan nuclear receptor Nr4a2/Nurr1.
Subtype specification of GABAergic amacrine cells by the orphan nuclear receptor Nr4a2/Nurr1.
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DOI：
10.1523/jneurosci.3048-09.2009
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发表时间：
2009-08-19
期刊：
影响因子：
--
通讯作者：
Xiang M
中科院分区：
文献类型：
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作者：
Jiang H;Xiang M
在哺乳动物视网膜中，无长突细胞（acrine cells，AC）包含许多具有极其不同的形态和生理功能的亚型。到目前为止，这些亚型如何在视网膜发生过程中出现在分子水平上仍然是未知的。孤儿核受体Nr4a2在指定腹侧中脑多巴胺能神经元中起重要作用，其突变与家族性帕金森病相关。在这里，我们表明，Nr4a2也是至关重要的参与AC亚型身份的规范。在小鼠视网膜发生过程中，Nr4a2在有丝分裂后GABA能AC及其前体的子集中表达。其靶向失活导致GABA能AC亚群的损失，包括所有多巴胺能和p57 Kip2+神经元以及钙结合蛋白+AC的同时增加。错误表达的Nr4a2可以促进GABA能AC分化并抑制钙结合蛋白+AC，而其显性负性形式具有抑制GABA能AC命运的能力。此外，Nr4a2的表达受Foxn4的正调控，受Brn3b的负控制，这两种视网膜生成因子先前分别被证明促进和抑制GABA能AC。这些数据表明，Nr4a2是必要的和足够的，赋予AC前体与GABA能AC表型的身份，它可以网络与多种其他视网膜因子，以确保适当的规格和AC神经递质亚型的分化。
In the mammalian retina, amacrine cells (ACs) contain numerous subtypes with extremely diverse morphologies and physiological functions. To date, how these subtypes arise during retinogenesis remains largely unknown at the molecular level. The orphan nuclear receptor Nr4a2 plays an essential role in specifying ventral midbrain dopaminergic neurons and its mutations are associated with familial Parkinson's disease. Here we show that Nr4a2 is also critically involved in the specification of AC subtype identity. During mouse retinogenesis, Nr4a2 is expressed in a subset of postmitotic GABAergic ACs and their precursors. Its targeted inactivation results in the loss of a subpopulation of GABAergic ACs that include all dopaminergic and p57Kip2+ neurons as well as a simultaneous increase of calbindin+ ACs. Misexpressed Nr4a2 can promote GABAergic AC differentiation and repress calbindin+ ACs, whereas its dominant-negative form has the ability to suppress the GABAergic AC fate. Moreover, the expression of Nr4a2 is positively regulated by Foxn4 and negatively controlled by Brn3b, two retinogenic factors previously shown to promote and suppress GABAergic ACs, respectively. These data suggest that Nr4a2 is both necessary and sufficient to confer AC precursors with the identity of a GABAergic AC phenotype, and that it may network with multiple other retinogenic factors to ensure proper specification and differentiation of AC neurotransmitter subtypes.