Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study.
Integration of structural MRI and epigenetic analyses hint at linked cellular defects of the subventricular zone and insular cortex in autism: Findings from a case study.
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DOI：
10.3389/fnins.2022.1023665
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发表时间：
2022
影响因子：
4.3
通讯作者：
Maunakea, Alika
中科院分区：
文献类型：
--
作者：
Takahashi, Emi;Allan, Nina;Peres, Rafael;Ortug, Alpen;van der Kouwe, Andre J. W.;Valli, Briana A.;Ethier, Elizabeth;Levman, Jacob K.;Baumer, Nicole;Tsujimura, Keita;Vargas-Maya, Nauru Idalia;McCracken, Trevor;Lee, Rosa;Maunakea, Alika
自闭症谱系障碍 (ASD) 是一种神经发育障碍，其特征是社交互动、沟通和重复、限制性行为缺陷，这些特征由皮质活动支持。鉴于侧脑室室下区 (SVZ) 对皮质发育的重要性，我们比较了 ASD 病例样本以及性别和年龄匹配的未受影响大脑中 SVZ 和相关皮质区域的分子、细胞和结构差异。我们对离体死后脑样本使用磁共振成像 (MRI) 和扩散纤维束成像，并通过全基因组亚硫酸氢盐测序 (WGBS)、流式细胞术和 RT qPCR 进一步分析。通过 MRI，我们观察到，与未受影响的对照组相比，ASD 诊断病例中从背侧 SVZ 的纤维束成像路径减少，从后腹侧 SVZ 到岛叶皮质的路径增加，以及岛叶皮质内的皮质厚度变化。在 ASD 病例中，往返于岛叶的长距离纤维束成像路径也减少了。基于 FACS 的细胞分选显示，相对于未受影响的对照，ASD 病例 SVZ 中的增殖细胞数量有所增加。 SVZ 组织的靶向 qPCR 检测表明，与对照相比，自闭症谱系障碍 (ASD) 神经元分化和迁移相关基因的表达水平显着降低。最后，利用全基因组 DNA 甲基化分析，我们确定了 19 个与神经发育、功能和疾病相关的基因，其中 7 个基因以前未在 ASD 中描述过，但在自闭症 SVZ 和岛叶样本中甲基化存在显着差异。这些发现提出了一个假设，即神经发育过程中的表观遗传变化改变了 SVZ 的增殖、迁移和分化轨迹，影响皮质结构和功能并导致 ASD 表型。
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction, communication and repetitive, restrictive behaviors, features supported by cortical activity. Given the importance of the subventricular zone (SVZ) of the lateral ventrical to cortical development, we compared molecular, cellular, and structural differences in the SVZ and linked cortical regions in specimens of ASD cases and sex and age-matched unaffected brain. We used magnetic resonance imaging (MRI) and diffusion tractography on ex vivo postmortem brain samples, which we further analyzed by Whole Genome Bisulfite Sequencing (WGBS), Flow Cytometry, and RT qPCR. Through MRI, we observed decreased tractography pathways from the dorsal SVZ, increased pathways from the posterior ventral SVZ to the insular cortex, and variable cortical thickness within the insular cortex in ASD diagnosed case relative to unaffected controls. Long-range tractography pathways from and to the insula were also reduced in the ASD case. FACS-based cell sorting revealed an increased population of proliferating cells in the SVZ of ASD case relative to the unaffected control. Targeted qPCR assays of SVZ tissue demonstrated significantly reduced expression levels of genes involved in differentiation and migration of neurons in ASD relative to the control counterpart. Finally, using genome-wide DNA methylation analyses, we identified 19 genes relevant to neurological development, function, and disease, 7 of which have not previously been described in ASD, that were significantly differentially methylated in autistic SVZ and insula specimens. These findings suggest a hypothesis that epigenetic changes during neurodevelopment alter the trajectory of proliferation, migration, and differentiation in the SVZ, impacting cortical structure and function and resulting in ASD phenotypes.
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影响因子：
16.2
作者：
Casingal CR;Descant KD;Anton ES
通讯作者：
Anton ES
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9.5
作者：
Dedeurwaerder S;Defrance M;Bizet M;Calonne E;Bontempi G;Fuks F
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Ward, Monika A.
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通讯作者：
RUTTER, M
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作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
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