Chromodomain helicase DNA-binding protein 8 (Chd8) is a high-confidence risk gene for autism spectrum disorder (ASD). However, how Chd8 haploinsufficiency impairs gene expression in the brain and impacts behavior at different stages of life is unknown. We generated a mutant mouse line with an ASD-linked loss-of-function mutation in Chd8 (V986*; stop codon mutation). We examined the behavior of Chd8 mutant mice along with transcriptional changes in the cerebral cortex as a function of age, with a focus on one embryonic (E14.5) and three postnatal ages (1, 6, and 12 months). Chd8V986*/+ mutant mice displayed macrocephaly, reduced rearing responses and reduced center time in the open field, and enhanced social novelty preference. Behavioral phenotypes were more evident in Chd8V986*/+ mutant mice at 1 year of age. Pup survival was reduced in wild-type x Chd8V986*/+ crosses when the mutant parent was female. Transcriptomic analyses indicated that pathways associated with synaptic and neuronal projections and sodium channel activity were reduced in the cortex of embryonic Chd8V986*/+ mice and then equalized relative to wild-type mice in the postnatal period. At 12 months of age, expression of genes associated with endoplasmic reticulum (ER) stress, chaperone-mediated protein folding, and the unfolded protein response (UPR) were reduced in Chd8V986*/+ mice, whereas genes associated with the c-MET signaling pathway were increased in expression. It is unclear whether the transcriptional changes observed with age in Chd8V986*/+ mice reflect a direct effect of CHD8-regulated gene expression, or if CHD8 indirectly affects the expression of UPR/ER stress genes in adult mice as a consequence of neurodevelopmental abnormalities. Collectively, these data suggest that UPR/ER stress pathways are reduced in the cerebral cortex of aged Chd8V986*/+ mice. Our study uncovers neurodevelopmental and age-related phenotypes in Chd8V986*/+ mice and highlights the importance of controlling for age when studying Chd8 haploinsufficient mice.

中文翻译：

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Chd8 单倍剂量不足会损害生命后期的早期大脑发育和蛋白质稳态

染色体解旋酶 DNA 结合蛋白 8 (Chd8) 是自闭症谱系障碍 (ASD) 的高置信度风险基因。然而，Chd8 单倍体不足如何损害大脑中的基因表达并影响生命不同阶段的行为尚不清楚。我们在 Chd8（V986*；终止密码子突变）中生成了一个具有 ASD 相关功能丧失突变的突变小鼠品系。我们检查了 Chd8 突变小鼠的行为以及大脑皮层中作为年龄函数的转录变化，重点是一个胚胎（E14.5）和三个出生后年龄（1、6 和 12 个月）。Chd8V986*/+ 突变小鼠表现出巨头畸形、减少饲养反应和减少开放领域的中心时间，并增强社会新奇偏好。行为表型在 Chd8V986*/+ 突变小鼠 1 岁时更为明显。当突变亲本为雌性时，野生型 x Chd8V986*/+ 杂交的幼崽存活率降低。转录组学分析表明，与突触和神经元投射以及钠通道活性相关的通路在胚胎 Chd8V986*/+ 小鼠的皮层中减少，然后在出生后与野生型小鼠相比变得相等。在 12 个月大时，Chd8V986*/+ 小鼠中与内质网 (ER) 应激、分子伴侣介导的蛋白质折叠和未折叠蛋白质反应 (UPR) 相关的基因表达降低，而与 c-MET 信号相关的基因表达通路表达增加。目前尚不清楚在 Chd8V986*/+ 小鼠中观察到的随年龄增长的转录变化是否反映了 CHD8 调节基因表达的直接影响，或者 CHD8 是否由于神经发育异常而间接影响成年小鼠中 UPR/ER 应激基因的表达。总的来说，这些数据表明，在老年 Chd8V986*/+ 小鼠的大脑皮层中，UPR/ER 应激通路减少。我们的研究揭示了 Chd8V986*/+ 小鼠的神经发育和年龄相关表型，并强调了在研究 Chd8 单倍体不足小鼠时控制年龄的重要性。