Nests of dividing neuroblasts sustain interneuron production for the developing human brain.
Nests of dividing neuroblasts sustain interneuron production for the developing human brain.
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DOI：
10.1126/science.abk2346
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发表时间：
2022-01-28
期刊：
影响因子：
--
通讯作者：
Huang EJ
中科院分区：
文献类型：
--
作者：
Paredes MF;Mora C;Flores-Ramirez Q;Cebrian-Silla A;Del Dosso A;Larimer P;Chen J;Kang G;Gonzalez Granero S;Garcia E;Chu J;Delgado R;Cotter JA;Tang V;Spatazza J;Obernier K;Ferrer Lozano J;Vento M;Scott J;Studholme C;Nowakowski TJ;Kriegstein AR;Oldham MC;Hasenstaub A;Garcia-Verdugo JM;Alvarez-Buylla A;Huang EJ
人类皮质含有来自内侧神经节隆起(MGE)的抑制性中间神经元，内侧神经节隆起是胚胎腹侧前脑的生发区。目前尚不清楚这个生发区是如何为人脑产生足够的中间神经元的。我们发现人类MGE(HMGE)含有增殖性神经母细胞巢，具有与hMGE中其他前体细胞不同的超微结构和转录特征。当分离的hMGE细胞被移植到新生小鼠的大脑中时，它们会转化为包含增殖的神经母细胞的巢，这些细胞产生年轻的神经元，这些神经元广泛迁移到小鼠的前脑，并成熟为不同类型的功能中间神经元。综上所述，这些结果表明，hMGE内神经母细胞的巢组织和持续增殖为人类前脑中间神经元的扩大产生提供了一种机制。胎儿期大脑腹侧的DCX+细胞巢。人类胚胎前脑冠状切面示意图，显示内侧神经节隆起(MGE，绿色)，内含DCX+细胞巢(窝，绿色)。巢蛋白+祖细胞(蓝色)存在于VZ和iSVZ内，并插入OSVZ(窝点所在的区域)。OSVZ的最初部分包含巢蛋白+前体细胞的栅栏，这些细胞被称为I型簇(淡蓝色细胞)。在OSVZ的外部，巢转变为迁移的DCX+细胞链；周围的Nestin+祖细胞排列成称为II型簇(白细胞)的细胞组。除了Nestin+前体细胞的增殖外，DCX+细胞之间还存在细胞分裂，这表明人类前脑中MGE来源的中间神经元的产生具有多种前体状态。大脑皮质中兴奋性和抑制性神经元(中间神经元)群之间的平衡促进了正常的大脑功能。中间神经元主要产生于胚胎前脑腹侧的内侧、尾侧和外侧神经节隆起(MGE、CGE和LGE)；这些亚区形成不同的中间神经元亚群。在啮齿动物中，MGE产生皮质中间神经元，即与兴奋性神经元相连的小白蛋白+(PV+)和生长抑素+(SST+)亚型，以调节它们的活动。中间神经元产生的缺陷与神经发育和精神障碍有关，包括自闭症、癫痫和精神分裂症。人类MGE(HMGE)是如何产生填充前脑所需的中间神经元数量的？HMGE包含不同于在啮齿动物MGE和人脑其他生发区观察到的祖细胞簇。这种细胞结构可能是理解神经元间神经发生的关键。我们从14周(GW)到39GW(足月)研究了发育中的hMGE内不同隔室的细胞和分子特性，以研究它们对抑制性中间神经元产生的贡献。我们开发了一种异种移植试验，以跟踪来自该生发区的人中间神经元的迁移和成熟。在hMGE内，密集排列的双重皮质素+(DCX+)和LHX6+细胞聚集体(巢)被巢蛋白+祖细胞及其突起包围。这些富含DCX+细胞的巢在hMGE内可见，而在邻近LGE内未见。我们发现DES内的细胞表达与年轻神经元相关的分子标记，如DCX和多唾液酸化神经细胞黏附分子(PSA-NCAM)。一个亚群也表达Ki-67，这是一个增殖的标志；因此，我们将这些细胞称为神经母细胞。DES内的一小部分DCX+细胞表达SOX2和E2F1，这是与祖细胞和增殖特性相关的转录因子。在hMGE中，超过20%的DCX+细胞处于分裂状态，尤其是在窝穴内。在整个胎儿期人脑发育过程中，牙窝内增殖的神经母细胞持续存在于hMGE中。透射电子显微镜和时间推移显微镜证实DCX+细胞分裂。电子显微镜显示窝穴内细胞之间的粘连接触，提供了多个位置将DEN细胞锚定在一起。窝窝内的神经母细胞表达PCDH19，窝窝周围的巢蛋白+祖细胞表达PCDH10；这些发现提示细胞的不同黏附在窝点的形成和维持中起作用。当被移植到新生小鼠的大脑中时，分离的hMGE细胞改造了含有增殖的DCX+细胞的Den，类似于在出生前观察到的人类大脑中的Den。这表明洞穴是由细胞自主机制产生的。除了形成洞穴，移植的hMGE来源的神经母细胞还产生了年轻的神经元，这些神经元广泛迁移到宿主小鼠大脑的皮质和皮质下区域。移植1年后，这些神经母细胞已分化为不同的γ-氨基丁酸表达(GABA能)中间神经元亚型，包括SST+和PV+细胞，表现出形态和功能的成熟。HMGE有洞穴，表达早期神经元标记的细胞继续分裂并产生GABA能中间神经元。这种MGE特异性的神经母细胞在人脑中的排列一直存在到出生，支持抑制神经元的扩大神经发生。鉴于该区域具有强大的神经源性输出，了解hMGE中皮质间神经元产生的机制将有助于深入了解最容易受到遗传或环境伤害的细胞类型和发育时期。
The human cortex contains inhibitory interneurons derived from the medial ganglionic eminence (MGE), a germinal zone in the embryonic ventral forebrain. How this germinal zone generates sufficient interneurons for the human brain remains unclear. We found that the human MGE (hMGE) contains nests of proliferative neuroblasts with ultrastructural and transcriptomic features that distinguish them from other progenitors in the hMGE. When dissociated hMGE cells are transplanted into the neonatal mouse brain, they reform into nests containing proliferating neuroblasts that generate young neurons that migrate extensively into the mouse forebrain and mature into different subtypes of functional interneurons. Together, these results indicate that the nest organization and sustained proliferation of neuroblasts in the hMGE provide a mechanism for the extended production of interneurons for the human forebrain. Nests of DCX+ cells in the ventral prenatal brain. Schematic of a coronal view of the embryonic human forebrain showing the medial ganglionic eminence (MGE, green), with nests of DCX+ cells (DENs, green). Nestin+ progenitor cells (blue) are present within the VZ and iSVZ and are intercalated in the oSVZ (where DENs reside). The initial segment of the oSVZ contains palisades of nestin+ progenitors referred to as type I clusters (light blue cells) around DENs. In the outer part of the oSVZ, DENs transition to chains of migrating DCX+ cells; surrounding nestin+ progenitors are arranged into groups of cells referred to as type II clusters (white cells). In addition to proliferation of nestin+ progenitors, cell division is present among DCX+ cells within DENs, suggesting multiple progenitor states for the generation of MGE-derived interneurons in the human forebrain. Balance between excitatory and inhibitory neuron (interneuron) populations in the cortex promotes normal brain function. Interneurons are primarily generated in the medial, caudal, and lateral ganglionic eminences (MGE, CGE, and LGE) of the ventral embryonic forebrain; these subregions give rise to distinct interneuron subpopulations. In rodents, the MGE generates cortical interneurons, the parvalbumin+ (PV+) and somatostatin+ (SST+) subtypes that connect with excitatory neurons to regulate their activity. Defects in interneuron production have been implicated in neurodevelopmental and psychiatric disorders including autism, epilepsy, and schizophrenia. How does the human MGE (hMGE) produce the number of interneurons required to populate the forebrain? The hMGE contains progenitor clusters distinct from what has been observed in the rodent MGE and other germinal zones of the human brain. This cytoarchitecture could be the key to understanding interneuron neurogenesis. We investigated the cellular and molecular properties of different compartments within the developing hMGE, from 14 gestational weeks (GW) to 39 GW (term), to study their contribution to the production of inhibitory interneurons. We developed a xenotransplantation assay to follow the migration and maturation of the human interneurons derived from this germinal region. Within the hMGE, densely packed aggregates (nests) of doublecortin+ (DCX+) and LHX6+ cells were surrounded by nestin+ progenitor cells and their processes. These DCX+ cell–enriched nests (DENs) were observed in the hMGE but not in the adjacent LGE. We found that cells within DENs expressed molecular markers associated with young neurons, such as DCX, and polysialylated neural cell adhesion molecule (PSA-NCAM). A subpopulation also expressed Ki-67, a marker of proliferation; therefore, we refer to these cells as neuroblasts. A fraction of DCX+ cells inside DENs expressed SOX2 and E2F1, transcription factors associated with progenitor and proliferative properties. More than 20% of DCX+ cells in the hMGE were dividing, specifically within DENs. Proliferating neuroblasts in DENs persisted in the hMGE throughout prenatal human brain development. The division of DCX+ cells was confirmed by transmission electron microscopy and time-lapse microscopy. Electron microscopy revealed adhesion contacts between cells within DENs, providing multiple sites to anchor DEN cells together. Neuroblasts within DENs express PCDH19, and nestin+ progenitors surrounding DENs express PCDH10; these findings suggest a role for differential cell adhesion in DEN formation and maintenance. When transplanted into the neonatal mouse brain, dissociated hMGE cells reformed DENs containing proliferative DCX+ cells, similar to DENs observed in the prenatal human brain. This suggests that DENs are generated by cell-autonomous mechanisms. In addition to forming DENs, transplanted hMGE-derived neuroblasts generated young neurons that migrated extensively into cortical and subcortical regions in the host mouse brain. One year after transplantation, these neuroblasts had differentiated into distinct γ-aminobutyric acid–expressing (GABAergic) interneuron subtypes, including SST+ and PV+ cells, that showed morphological and functional maturation. The hMGE harbors DENs, where cells expressing early neuronal markers continue to divide and produce GABAergic interneurons. This MGE-specific arrangement of neuroblasts in the human brain is present until birth, supporting expanded neurogenesis for inhibitory neurons. Given the robust neurogenic output from this region, knowledge of the mechanisms underlying cortical interneuron production in the hMGE will provide insights into the cell types and developmental periods that are most vulnerable to genetic or environmental insults.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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