Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.
Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes.
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DOI：
10.1038/s41467-022-33364-z
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发表时间：
2022-10-06
影响因子：
16.6
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中科院分区：
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人类端脑是一种进化上先进的大脑结构，与许多独特的人类行为和疾病有关。然而，与人类端脑发育有关的细胞谱系和分子通路在很大程度上仍然未知。我们从干细胞来源的单个神经元中产生人类端脑类器官，并研究正常和病理条件下的端脑发育。我们发现，单一的神经玫瑰花衍生的类器官包含苍白球和subpallial神经祖细胞，兴奋性和抑制性神经元，以及大胶质细胞和内皮细胞周围，并表现出可预测的组织和细胞结构。我们全面表征了SNR衍生类器官中神经元的特性，并从端脑发育早期的NP共同库中确定了与兴奋性和抑制性神经谱系规范相关的转录程序。我们还证明，类器官中的神经元与自闭症和智力残疾相关基因SHANK 3的半合子缺失表现出内在的和兴奋性突触缺陷和受损的几个簇原钙粘蛋白的表达。总的来说，本研究验证了SNR衍生的类器官作为研究人类端脑皮质-纹状体发育的可靠模型，并鉴定了具有SHANK 3半合子的人类端脑组织中的内在、突触和簇状原钙粘蛋白表达缺陷。我们对健康和疾病中人类大脑发育的理解是有限的。作者从干细胞衍生的分离的单个神经元中产生人脑类器官，以研究SHANK 3中自闭症相关遗传异常引起的人类皮质-纹状体发育和缺陷。
Human telencephalon is an evolutionarily advanced brain structure associated with many uniquely human behaviors and disorders. However, cell lineages and molecular pathways implicated in human telencephalic development remain largely unknown. We produce human telencephalic organoids from stem cell-derived single neural rosettes and investigate telencephalic development under normal and pathological conditions. We show that single neural rosette-derived organoids contain pallial and subpallial neural progenitors, excitatory and inhibitory neurons, as well as macroglial and periendothelial cells, and exhibit predictable organization and cytoarchitecture. We comprehensively characterize the properties of neurons in SNR-derived organoids and identify transcriptional programs associated with the specification of excitatory and inhibitory neural lineages from a common pool of NPs early in telencephalic development. We also demonstrate that neurons in organoids with a hemizygous deletion of an autism- and intellectual disability-associated gene SHANK3 exhibit intrinsic and excitatory synaptic deficits and impaired expression of several clustered protocadherins. Collectively, this study validates SNR-derived organoids as a reliable model for studying human telencephalic cortico-striatal development and identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity. Our understanding of human brain development in health and disease is limited. The authors generated human brain organoids from stem cell-derived isolated single neural rosettes to study human cortico-striatal development and deficits caused by an autism-associated genetic abnormality in SHANK3.
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