Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.
MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
J Anat. 2018 Dec;233(6):755-769. doi: 10.1111/joa.12889. Epub 2018 Oct 2.
Recent large-scale exome sequencing studies have identified mutations in several members of the CHD (Chromodomain Helicase DNA-binding protein) gene family in neurodevelopmental disorders. Mutations in the CHD2 gene have been linked to developmental delay, intellectual disability, autism and seizures, CHD8 mutations to autism and intellectual disability, whereas haploinsufficiency of CHD7 is associated with executive dysfunction and intellectual disability. In addition to these neurodevelopmental features, a wide range of other developmental defects are associated with mutants of these genes, especially with regards to CHD7 haploinsufficiency, which is the primary cause of CHARGE syndrome. Whilst the developmental expression of CHD7 has been reported previously, limited information on the expression of CHD2 and CHD8 during development is available. Here, we compare the expression patterns of all three genes during mouse development directly. We find high, widespread expression of these genes at early stages of development that gradually becomes restricted during later developmental stages. Chd2 and Chd8 are widely expressed in the developing central nervous system (CNS) at all stages of development, with moderate expression remaining in the neocortex, hippocampus, olfactory bulb and cerebellum of the postnatal brain. Similarly, Chd7 expression is seen throughout the CNS during late embryogenesis and early postnatal development, with strong enrichment in the cerebellum, but displays low expression in the cortex and neurogenic niches in early life. In addition to expression in the brain, novel sites of Chd2 and Chd8 expression are reported. These findings suggest additional roles for these genes in organogenesis and predict that mutation of these genes may predispose individuals to a range of other, non-neurological developmental defects.
最近的大规模外显子组测序研究已经在神经发育障碍中鉴定出几个 CHD（染色质域解旋酶 DNA 结合蛋白）基因家族成员的突变。CHD2 基因突变与发育迟缓、智力障碍、自闭症和癫痫有关，CHD8 基因突变与自闭症和智力障碍有关，而 CHD7 的单倍不足与执行功能障碍和智力障碍有关。除了这些神经发育特征外，这些基因的突变体还与广泛的其他发育缺陷有关，特别是 CHD7 单倍不足，这是 CHARGE 综合征的主要原因。虽然之前已经报道了 CHD7 的发育表达，但关于 CHD2 和 CHD8 在发育过程中的表达信息有限。在这里，我们直接比较了这三个基因在小鼠发育过程中的表达模式。我们发现这些基因在发育早期具有高度广泛的表达，随着发育后期的进行，表达逐渐受到限制。Chd2 和 Chd8 在发育中的中枢神经系统（CNS）中广泛表达，在发育的各个阶段都有中等程度的表达，在出生后的大脑新皮质、海马体、嗅球和小脑中仍有表达。同样，Chd7 在胚胎晚期和出生后早期的整个 CNS 中表达，在小脑中强烈富集，但在皮质和神经发生龛中表达较低。除了在大脑中的表达外，还报道了 Chd2 和 Chd8 的新表达部位。这些发现表明这些基因在器官发生中具有额外的作用，并预测这些基因的突变可能使个体易患一系列其他非神经发育缺陷。
