Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.
Cerebral organoids reveal early cortical maldevelopment in schizophrenia-computational anatomy and genomics, role of FGFR1.
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DOI：
10.1038/s41398-017-0054-x
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发表时间：
2017-11-17
影响因子：
6.8
通讯作者：
Stachowiak MK
中科院分区：
文献类型：
--
作者：
Stachowiak EK;Benson CA;Narla ST;Dimitri A;Chuye LEB;Dhiman S;Harikrishnan K;Elahi S;Freedman D;Brennand KJ;Sarder P;Stachowiak MK
对来自精神分裂症患者和对照个体的诱导多能干细胞（iPSC）的研究表明，该疾病在前神经元阶段被编程，涉及常见的失调mRNA转录组，并确定了整合核FGFR1信号传导是常见的失调机制。我们使用来自四名对照和三名精神分裂症患者的人胚胎干细胞（hESC）和iPSC衍生的脑类器官来模拟子宫内脑发育的前三个月。精神分裂症类器官揭示了从心室区（VZ）到整个中间区（IZ）和皮质区（CZ）的增殖Ki67+神经祖细胞（NPC）的异常分散。TBR1先驱神经元和reelin，引导皮质花瓣迁移，被限制从精神分裂症皮层。成熟的神经元在皮层下区域大量发育，但在精神分裂症皮层中却被耗尽。皮质内连接性的下降表示的方向和形态的变化calretinin中间神经元。在精神分裂症类器官中，发育中的皮质下细胞大量表达核（n）FGFR1，但CZ的神经元定向细胞（NCC）中表达减少。显性负性和组成型活性nFGFR 1的转染引起hESC衍生的NPC和NCC中神经个体发生基因网络的广泛破坏。fgfr 1基因是NPC和NCC中表达的最突出的FGFR基因，用PD173074阻断可再现hESC脑类器官中nFGFR 1和皮质神经元成熟的丧失。我们首次报道了精神分裂症皮质畸形的进展，并将其与FGFR1信号的改变联系起来。针对INFS可能提供精神分裂症的预防性治疗。
Studies of induced pluripotent stem cells (iPSCs) from schizophrenia patients and control individuals revealed that the disorder is programmed at the preneuronal stage, involves a common dysregulated mRNA transcriptome, and identified Integrative Nuclear FGFR1 Signaling a common dysregulated mechanism. We used human embryonic stem cell (hESC) and iPSC-derived cerebral organoids from four controls and three schizophrenia patients to model the first trimester of in utero brain development. The schizophrenia organoids revealed an abnormal scattering of proliferating Ki67+ neural progenitor cells (NPCs) from the ventricular zone (VZ), throughout the intermediate (IZ) and cortical (CZ) zones. TBR1 pioneer neurons and reelin, which guides cortico-petal migration, were restricted from the schizophrenia cortex. The maturing neurons were abundantly developed in the subcortical regions, but were depleted from the schizophrenia cortex. The decreased intracortical connectivity was denoted by changes in the orientation and morphology of calretinin interneurons. In schizophrenia organoids, nuclear (n)FGFR1 was abundantly expressed by developing subcortical cells, but was depleted from the neuronal committed cells (NCCs) of the CZ. Transfection of dominant negative and constitutively active nFGFR1 caused widespread disruption of the neuro-ontogenic gene networks in hESC-derived NPCs and NCCs. The fgfr1 gene was the most prominent FGFR gene expressed in NPCs and NCCs, and blocking with PD173074 reproduced both the loss of nFGFR1 and cortical neuronal maturation in hESC cerebral organoids. We report for the first time, progression of the cortical malformation in schizophrenia and link it to altered FGFR1 signaling. Targeting INFS may offer a preventive treatment of schizophrenia.
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影响因子：
6.6
作者：
Blanchard, Jack J.;Kring, Ann M.;Gur, Raquel
通讯作者：
Gur, Raquel
影响因子：
11.1
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Coleman, Stacey J.;Chioni, Athina-Myrto;Ghallab, Mohammed;Anderson, Rhys K.;Lemoine, Nicholas R.;Kocher, Hemant M.;Grose, Richard P.
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通讯作者：
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作者：
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通讯作者：
Gottesman, II
影响因子：
4.8
作者：
Fang, XH;Stachowiak, EK;Stachowiak, MK
通讯作者：
Stachowiak, MK