The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation.
The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation.
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DOI：
10.1016/j.stemcr.2018.07.014
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发表时间：
2018-09-11
影响因子：
5.9
通讯作者：
Arenas E
中科院分区：
文献类型：
--
作者：
Gyllborg D;Ahmed M;Toledo EM;Theofilopoulos S;Yang S;Ffrench-Constant C;Arenas E
中脑多巴胺能神经元的发育受多种形态因子和转录因子的调控。然而，人们对细胞外基质蛋白在这一过程中的作用知之甚少。在这里，我们研究了屋顶板特异的海绵蛋白(Rspo1-4)和地板特异的Spin1(SPON1)的功能。在丙二醛神经发生过程中，只有RSPO2和SPON1高水平表达，而LGR5受体在中脑底板前体细胞中表达。令人惊讶的是，在小鼠原代培养和胚胎干细胞(ESCs)中，RSPO2而不是SPON1特异性地促进丙二醛神经母细胞分化为丙二醛神经元。此外，还发现RSPO2不仅能促进人胚胎干细胞向丙二醛分化，还能促进丙二醛的神经发生。因此，我们的结果揭示了基质细胞蛋白RSPO2的一个意想不到的功能，并建议将其应用于改善人类干细胞制剂中的丙二醛神经发生和分化，以用于细胞替代治疗或帕金森病的药物开发。Rsp2在中脑多巴胺能神经元发育过程中动态表达，RSPO2促进培养的小鼠神经元的多巴胺能分化，RSPO2增加人ESCs的多巴胺能神经发生和分化，Gyllborg及其同事报道了配对细胞蛋白R-响应蛋白2(RSPO2)在多巴胺能神经元发育中的功能。RSPO2在中脑发育过程中动态表达，促进小鼠和人神经母细胞的多巴胺能分化。此外，他们还表明，RSPO2诱导了人类干细胞培养中的多巴胺能神经发生，这表明RSPO2可能应用于帕金森病的细胞替代策略。
The development of midbrain dopaminergic (mDA) neurons is controlled by multiple morphogens and transcription factors. However, little is known about the role of extracellular matrix proteins in this process. Here we examined the function of roof plate-specific spondins (RSPO1-4) and the floor plate-specific, spondin 1 (SPON1). Only RSPO2 and SPON1 were expressed at high levels during mDA neurogenesis, and the receptor LGR5 was expressed by midbrain floor plate progenitors. Surprisingly, RSPO2, but not SPON1, specifically promoted the differentiation of mDA neuroblasts into mDA neurons in mouse primary cultures and embryonic stem cells (ESCs). In addition, RSPO2 was found to promote not only mDA differentiation, but also mDA neurogenesis in human ESCs. Our results thus uncover an unexpected function of the matricellular protein RSPO2 and suggest an application to improve mDA neurogenesis and differentiation in human stem cell preparations destined to cell replacement therapy or drug discovery for Parkinson disease. Rspo2 is dynamically expressed during midbrain dopaminergic neuron development RSPO2 promotes the dopaminergic differentiation of mouse neurons in culture RSPO2 increases dopaminergic neurogenesis and differentiation of human ESCs Gyllborg and colleagues report on the function of the matricellular protein R-Spondin 2 (RSPO2) in dopaminergic neuron development. RSPO2 is dynamically expressed during midbrain development and promotes the dopaminergic differentiation of mouse and human neuroblasts. Furthermore, they show that RSPO2 induced dopaminergic neurogenesis in human stem cell cultures, suggesting a possible application of RSPO2 in cell replacement strategies for Parkinson disease.
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