Two parallel neural ectoderm progenitors contribute to the developing brain
Two parallel neural ectoderm progenitors contribute to the developing brain
两种平行的神经外胚层祖细胞共同构建了发育中的大脑
For centuries, scientists have thought of the brain as a single, unified organ. But new research led by Stanford Medicine reveals that what we call the brain is two distinct organs that evolved independently over hundreds of millions of years. 几个世纪以来，科学家一直认为大脑是一个单一的统一器官。但由斯坦福大学医学院领导的一项新研究揭示，我们所称的大脑实际上是两个在数亿年间独立进化的不同器官。
The discovery overturns a prevailing model of brain development. For decades researchers have subscribed to the theory that there is a single progenitor cell early in development that gives rise to the entire brain. This model suggested all parts of the brain shared a common developmental origin. 这一发现推翻了主流的大脑发育模型。几十年来，研究人员一直认同这样一种理论：在发育早期存在单一的祖细胞，它衍生出了整个大脑。该模型认为大脑的所有部分都有共同的发育起源。
The new research finding shows that the human brain consists of two ancient nervous systems cleverly packaged together — a more primitive part that regulates our hearts’ beating, our breathing and other functions, and another that makes us distinctly human, capable of poetry, mathematics and wondering about our own origins. 这项新研究发现，人类大脑由两个巧妙结合在一起的古老神经系统组成——一个负责调节心跳、呼吸和其他功能的原始部分，以及另一个使我们成为人类、能够进行诗歌创作、数学运算并思考自身起源的部分。
The discovery could help explain why scientists have struggled for decades to grow certain types of brain cells in the laboratory — and it opens new avenues for studying devastating diseases that affect the brain stem, such as spinal muscular atrophy (also known as SMA) and amyotrophic lateral sclerosis (also known as ALS or Lou Gehrig’s disease). 这一发现有助于解释为什么科学家几十年来一直难以在实验室中培养某些类型的脑细胞，并为研究影响脑干的毁灭性疾病开辟了新途径，例如脊髓性肌萎缩症（SMA）和肌萎缩侧索硬化症（ALS，即渐冻症）。
“We’ve shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain,” said Kyle Loh, PhD, associate professor of developmental biology. “Our discovery means that we can now grow neurons from the back of the brain, the hindbrain, in a petri dish and study their functions.” “我们首次证明，大脑前部和后部是由完全不同的祖细胞发育而来的，”发育生物学副教授、博士 Kyle Loh 表示。“我们的发现意味着，我们现在可以在培养皿中培养大脑后部（后脑）的神经元，并研究它们的功能。”
The findings were published in Nature Neuroscience Sept. 18. Loh is the senior author. Graduate students Carolyn Dundes and Rayyan Jokhai are co-first authors of the research. 该研究结果于 9 月 18 日发表在《自然-神经科学》（Nature Neuroscience）杂志上。Loh 是资深作者，研究生 Carolyn Dundes 和 Rayyan Jokhai 是该研究的共同第一作者。
Two brains
两个大脑
The adult brain has three main regions: the forebrain, midbrain and hindbrain. The forebrain handles higher-level thinking — language, consciousness and abstract reasoning. In contrast, the hindbrain, located at the back of the skull and often called the brain stem, controls essential, automatic functions that keep us alive: breathing, sleeping, and regulating our heartbeat and hunger urges. The hindbrain neurons also control the muscles of the face, tongue and throat, which affect speech and swallowing. 成年大脑有三个主要区域：前脑、中脑和后脑。前脑负责高级思维，如语言、意识和抽象推理。相比之下，位于颅骨后部、通常被称为脑干的后脑，控制着维持我们生存的基本自动功能：呼吸、睡眠以及调节心跳和饥饿感。后脑神经元还控制着面部、舌头和喉咙的肌肉，这些肌肉影响着说话和吞咽。
Despite the critical importance of the hindbrain, scientists have struggled for decades to generate human hindbrain neurons in the laboratory. This gap has hampered research into devastating diseases affecting the brain stem, including spinal muscular atrophy and amyotrophic lateral sclerosis. 尽管后脑至关重要，但科学家几十年来一直难以在实验室中生成人类后脑神经元。这一空白阻碍了对影响脑干的毁灭性疾病（包括脊髓性肌萎缩症和肌萎缩侧索硬化症）的研究。
SMA is a leading genetic cause of death in children under 1 year of age. ALS, which is often diagnosed between the ages of 40 and 70, affects both the forebrain and the hindbrain. In both disorders, certain hindbrain neurons gradually cease to function, and the patient loses the ability to swallow, which can cause pneumonia when food or liquid is inhaled into the lungs; eventually, patients lose the ability to breathe. SMA 是导致 1 岁以下儿童死亡的主要遗传原因。ALS 通常在 40 至 70 岁之间被诊断出来，会同时影响前脑和后脑。在这两种疾病中，某些后脑神经元会逐渐停止工作，患者失去吞咽能力，当食物或液体被吸入肺部时可能导致肺炎；最终，患者会失去呼吸能力。
The researchers’ breakthrough came from studying the earliest moments of embryonic development, during a stage called gastrulation when the body first takes shape. Jokhai and Dundes discovered that the hindbrain follows a separate developmental path, running in parallel to — rather than branching off from — the pathway that creates the forebrain and midbrain. 研究人员的突破来自于对胚胎发育最初时刻的研究，即身体初具雏形的“原肠胚形成”阶段。Jokhai 和 Dundes 发现，后脑遵循着一条独立的发育路径，它与构建前脑和中脑的路径是平行的，而不是从后者分支出来的。
The researchers learned this from examining developing mouse embryos. They identified two different brain progenitor cells. One, which expresses a gene called Otx2, is destined to become the forebrain and midbrain. The other, which expresses a gene called Gbx2, is committed to forming the hindbrain. They showed that these two cell populations never overlap; they are mutually exclusive from the earliest stages of development. 研究人员通过检查发育中的小鼠胚胎得出了这一结论。他们确定了两种不同的大脑祖细胞。一种表达名为 Otx2 的基因，注定要发育成前脑和中脑；另一种表达名为 Gbx2 的基因，致力于形成后脑。他们证明了这两个细胞群从不重叠；它们从发育的最早阶段起就是相互排斥的。
The team then examined the DNA packaging, or chromatin, in these cells. Chromatin is a way cells determine which genes can be easily accessed and which are bundled away out of reach. What they found was striking: The anterior neural ectoderm (future forebrain and midbrain) and posterior neural ectoderm (future hindbrain) have fundamentally different chromatin configurations. These differences essentially locked each progenitor cell into its respective fate, like travelers on parallel tracks that never cross. 随后，研究团队检查了这些细胞中的 DNA 包装（即染色质）。染色质是细胞决定哪些基因可以被轻易访问、哪些基因被捆绑在无法触及之处的一种方式。他们的发现令人震惊：前神经外胚层（未来的前脑和中脑）和后神经外胚层（未来的后脑）具有根本不同的染色质构型。这些差异本质上将每个祖细胞锁定在各自的命运中，就像在永不交叉的平行轨道上行驶的旅客。
“Previous attempts to make hindbrain neurons likely tried to coax forebrain and midbrain progenitors into hindbrain cells, which our study shows is not possible,” Jokhai said. This revelation explained decades of frustration in the field — scientists had been trying to turn one type of progenitor cell into another that it is fundamentally incapable of becoming. “之前制造后脑神经元的尝试，很可能是试图诱导前脑和中脑祖细胞转化为后脑细胞，而我们的研究表明这是不可能的，”Jokhai 说。这一发现解释了该领域几十年来令人沮丧的原因——科学家们一直试图将一种祖细胞转化为它从根本上无法变成的另一种细胞。
“In stem cell biology, people are always fixated with creating the end cell type, like the neuron,” Jokhai said. “But it’s important to begin at the earliest stages of embryonic development. Our careful attention to that early time point allowed us to find this fundamental split in brain development.” “在干细胞生物学中，人们总是专注于创造最终的细胞类型，比如神经元，”Jokhai 说。“但从胚胎发育的最早阶段开始研究非常重要。我们对那个早期时间点的仔细关注，使我们发现了大脑发育中这一根本性的分裂。”
Growing hindbrain neurons
培养后脑神经元
Armed with this knowledge, the researchers for the first time successfully coaxed human pluripotent stem cells (a kind of cell that can create any cell in the human body) to become functional hindbrain motor neurons in the laboratory. These lab-grown neurons displayed all the hallmarks of authentic hindbrain cells: They exhibited waves of electrical activity called action potentials and made proteins that identify the segments of the hindbrain that control facial and swallowing muscles. 掌握了这些知识后，研究人员首次成功地在实验室中诱导人类多能干细胞（一种可以制造人体任何细胞的细胞）转化为功能性的后脑运动神经元。这些实验室培养的神经元展示了真实后脑细胞的所有特征：它们表现出被称为动作电位的电活动波，并产生了能够识别控制面部和吞咽肌肉的后脑节段的蛋白质。
Finally, the researchers looked back over 550 million years of evolutionary time. They found the same two-origin brain pattern in chickens; zebrafish; and, remarkably, in acorn worms, tiny creatures living on the ocean floor that share a distant common ancestor with humans. Jellyfish, which diverged from humans about 600 to 700 million years ago, have two nervous systems at different ends of their body. 最后，研究人员回顾了 5.5 亿年的进化史。他们在鸡、斑马鱼以及生活在海底、与人类拥有共同远祖的微小生物——柱头虫身上，发现了同样的大脑双起源模式。而大约在 6 亿至 7 亿年前与人类分化的水母，其身体两端也拥有两个神经系统。
“Our research suggests that evolution took two existing neural systems and pushed them together spatially,” Loh said. “我们的研究表明，进化过程将两个现有的神经系统在空间上合并在了一起，”Loh 说。