Pervasive cortical and white matter anomalies in a mouse model for CHARGE syndrome.
Pervasive cortical and white matter anomalies in a mouse model for CHARGE syndrome.
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CHARGE（眼缺损、心脏缺陷、软骨闭锁、生长迟缓、生殖器异常和耳异常）综合征是由编码CHD 7（ATP依赖性染色质重塑因子）的基因突变引起的疾病，其特征在于多种先天性异常。这些包括一系列神经解剖学共病，可能是与CHARGE综合征相关的各种神经发育障碍的基础，包括智力残疾、运动协调缺陷、执行功能障碍和自闭症谱系障碍。在CHARGE综合征患者中进行颅骨成像研究具有挑战性，但小鼠模型中的高通量磁共振成像（MRI）技术可以无偏地识别神经解剖缺陷。在这里，我们提出了一个全面的神经解剖调查Chd 7单倍不足的小鼠模型的CHARGE综合征。我们的研究揭示了广泛的大脑发育不全和整个大脑中白色物质体积的减少。发育不全的严重程度在新皮质的后部区域比前部区域更明显。我们还通过扩散张量成像（DTI）对该模型中的白色物质束完整性进行了首次评估，以评估髓鞘广泛减少的潜在功能后果，这表明存在白色物质完整性缺陷。为了确定白色改变是否与细胞变化相对应，我们对出生后胼胝体中的少突胶质细胞谱系细胞进行了定量，发现成熟少突胶质细胞数量减少。总之，这些结果为CHARGE综合征患者未来的颅脑成像研究提供了一系列有希望的重点途径。成年Chd 7 Gt/+小鼠脑中广泛发育不全。通过高分辨率7 T结构MRI对突变型和野生型成年大脑进行比较，发现突变型小鼠的脑体积相对于野生型同窝仔（蓝色）减少。人类CHARGE综合征中受影响的多个结构（例如，嗅球和视束）发育不良，并且总白色物质和总灰质在Chd 7突变体中均显著减少。
CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital anomalies and Ear abnormalities) syndrome is a disorder caused by mutations in the gene encoding CHD7, an ATP dependent chromatin remodelling factor, and is characterised by a diverse array of congenital anomalies. These include a range of neuroanatomical comorbidities which likely underlie the varied neurodevelopmental disorders associated with CHARGE syndrome, which include intellectual disability, motor coordination deficits, executive dysfunction, and autism spectrum disorder. Cranial imaging studies are challenging in CHARGE syndrome patients, but high‐throughput magnetic resonance imaging (MRI) techniques in mouse models allow for the unbiased identification of neuroanatomical defects. Here, we present a comprehensive neuroanatomical survey of a Chd7 haploinsufficient mouse model of CHARGE syndrome. Our study uncovered widespread brain hypoplasia and reductions in white matter volume across the brain. The severity of hypoplasia appeared more pronounced in posterior areas of the neocortex compared to anterior regions. We also perform the first assessment of white matter tract integrity in this model through diffusion tensor imaging (DTI) to assess the potential functional consequences of widespread reductions in myelin, which suggested the presence of white matter integrity defects. To determine if white matter alterations correspond to cellular changes, we quantified oligodendrocyte lineage cells in the postnatal corpus callosum, uncovering reduced numbers of mature oligodendrocytes. Together, these results present a range of promising avenues of focus for future cranial imaging studies in CHARGE syndrome patients. Widespread hypoplasia in the brains of adult Chd7Gt/+ mice. A comparison of mutant and wildtype adult brains by high‐resolution 7 T structural MRI found a reduction in brain volume of mutant mice relative to wildtype littermates (coloured in blue). Multiple structures affected in human CHARGE syndrome (e.g., olfactory bulbs and optic tract) are hypoplastic and both total white matter and total grey matter were significantly reduced in Chd7 mutants.
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