Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143.
Department of Animal Science, University of California Davis, Davis, California 94143.
J Neurosci. 2021 Apr 7;41(14):3105-3119. doi: 10.1523/JNEUROSCI.2738-20.2021. Epub 2021 Feb 26.
Interneurons contribute to the complexity of neural circuits and maintenance of normal brain function. Rodent interneurons originate in embryonic ganglionic eminences, but developmental origins in other species are less understood. Here, we show that transcription factor expression patterns in porcine embryonic subpallium are similar to rodents, delineating a distinct medial ganglionic eminence (MGE) progenitor domain. On the basis of Nkx2.1, Lhx6, and Dlx2 expression, differentiation into neurons expressing GABA, and robust migratory capacity in explant assays, we propose that cortical and hippocampal interneurons originate from a porcine MGE region. Following xenotransplantation into adult male and female rat hippocampus, we further demonstrate that porcine MGE progenitors, like those from rodents, migrate and differentiate into morphologically distinct interneurons expressing GABA. Our findings reveal that basic rules for interneuron development are conserved across species, and that porcine embryonic MGE progenitors could serve as a valuable source for interneuron-based xenotransplantation therapies. Here we demonstrate that porcine medial ganglionic eminence, like rodents, exhibit a distinct transcriptional and interneuron-specific antibody profile, migratory capacity and are amenable to xenotransplantation. This is the first comprehensive examination of embryonic interneuron origins in the pig; and because a rich neurodevelopmental literature on embryonic mouse medial ganglionic eminence exists (with some additional characterizations in other species, e.g., monkey and human), our work allows direct neurodevelopmental comparisons with this literature.
中间神经元有助于神经回路的复杂性和正常大脑功能的维持。啮齿动物中间神经元起源于胚胎神经节隆起，但其他物种的发育起源了解较少。在这里，我们表明猪胚胎下丘脑中的转录因子表达模式与啮齿动物相似，描绘了一个独特的内侧神经节隆起（MGE）祖细胞域。基于 Nkx2.1、Lhx6 和 Dlx2 的表达、分化为表达 GABA 的神经元，以及在体外培养物中的强大迁移能力，我们提出皮质和海马中间神经元起源于猪 MGE 区域。在将猪 MGE 祖细胞异种移植到成年雄性和雌性大鼠海马体后，我们进一步证明，猪 MGE 祖细胞与啮齿动物一样，迁移并分化为表达 GABA 的形态独特的中间神经元。我们的研究结果表明，中间神经元发育的基本规则在物种间是保守的，并且猪胚胎 MGE 祖细胞可以作为基于中间神经元的异种移植治疗的有价值来源。在这里，我们证明猪的内侧神经节隆起与啮齿动物一样，表现出独特的转录和中间神经元特异性抗体特征、迁移能力，并适合异种移植。这是对猪胚胎中间神经元起源的首次全面检查；并且由于在胚胎鼠内侧神经节隆起上存在丰富的神经发育文献（在其他物种中也有一些特征，例如猴子和人类），我们的工作允许与该文献进行直接的神经发育比较。
