Department of Physiology and Biophysics, State University of New York at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14214, USA.
Brain. 2022 Sep 14;145(9):3250-3263. doi: 10.1093/brain/awac152.
ADNP and POGZ are two top-ranking risk factors for autism spectrum disorder and intellectual disability, but how they are linked to these neurodevelopmental disorders is largely unknown. Both ADNP and POGZ are chromatin regulators, which could profoundly affect gene transcription and cellular function in the brain. Using post-mortem tissue from patients with autism spectrum disorder, we found diminished expression of ADNP and POGZ in the prefrontal cortex, a region highly implicated in neurodevelopmental disorders. To understand the functional role of these neurodevelopmental disorder risk factors, we used viral-based gene transfer to investigate how Adnp or Pogz deficiency in mouse prefrontal cortex affects behavioural, transcriptomic and synaptic function. Mice with prefrontal cortex deficiency of Adnp or Pogz exhibited specific impairment of cognitive task performance. RNA-sequencing revealed that Adnp or Pogz deficiency induced prominent upregulation of overlapping genes enriched in neuroinflammation, similar to the elevation of pro-inflammatory genes in humans with neurodevelopmental disorders. Concomitantly, Adnp or Pogz deficiency led to the significant increase of pro-phagocytic microglial activation in prefrontal cortex, as well as the significant decrease of glutamatergic transmission and postsynaptic protein expression. These findings have uncovered the convergent functions of two top risk factors for autism spectrum disorder and intellectual disability in prefrontal cortex, providing a mechanism linking chromatin, transcriptional and synaptic dysregulation to cognitive deficits associated with neurodevelopmental disorders.
ADNP 和 POGZ 是自闭症谱系障碍和智力障碍的两个首要风险因素，但它们与这些神经发育障碍的关联在很大程度上尚不清楚。ADNP 和 POGZ 都是染色质调节剂，它们可能会深刻影响大脑中的基因转录和细胞功能。我们使用自闭症谱系障碍患者的死后组织，发现 ADNP 和 POGZ 在大脑前额叶皮质中的表达减少，而前额叶皮质高度参与神经发育障碍。为了了解这些神经发育障碍风险因素的功能作用，我们使用基于病毒的基因转移来研究小鼠前额叶皮质中 Adnp 或 Pogz 的缺失如何影响行为、转录组和突触功能。前额叶皮质中 Adnp 或 Pogz 缺失的小鼠表现出特定的认知任务表现受损。RNA 测序显示，Adnp 或 Pogz 的缺失诱导了重叠基因的显著上调，这些基因富集在神经炎症中，类似于神经发育障碍患者中促炎基因的升高。同时，Adnp 或 Pogz 的缺失导致前额叶皮质中促吞噬性小胶质细胞的激活显著增加，以及谷氨酸能传递和突触后蛋白表达的显著减少。这些发现揭示了自闭症谱系障碍和智力障碍的两个首要风险因素在前额叶皮质中的趋同功能，为染色质、转录和突触调节与神经发育障碍相关的认知缺陷之间的联系提供了机制。
