KAT6A deficiency impairs cognitive functions through suppressing RSPO2/Wnt signaling in hippocampal CA3 [RNA-seq]

Intellectual disability (ID) affects ~2% of the population and ID-associated genes are enriched for epigenetic factors, including those encoding the largest family of histone lysine acetyltransferases (KAT5-KAT8). Among them is KAT6A, whose mutations cause KAT6A Syndrome, with ID as a common clinical feature. However, the underlying molecular mechanism remains unknown. Here, we find that KAT6A deficiency impairs synaptic structure and plasticity in hippocampal CA3, but not in CA1 region, resulting in memory deficits in mice. We further identify a CA3-enriched gene Rspo2, encoding Wnt activator R-spondin 2, as a key transcriptional target of KAT6A. Importantly, deletion of Rspo2 in excitatory neurons impairs memory formation, and restoring RSPO2 expression in CA3 rescues the deficits in Wnt signaling and learning-associated behaviors in Kat6a mutant mice. Collectively, our results demonstrate that KAT6A-RSPO2-Wnt signaling plays a critical role in regulating hippocampal CA3 synaptic plasticity and cognitive function, providing potential therapeutic targets for KAT6A Syndrome and related neurodevelopmental diseases. Hippocampal tissues mRNA profiles of adult Control (wild type) and Kat6a+/- mice were generated by RNA-seq, using Illumina NovaSeq 6000智力障碍（Intellectual Disability, ID）影响约2%的人群，且ID相关基因富集于表观遗传因子，其中涵盖编码最大组蛋白赖氨酸乙酰转移酶（histone lysine acetyltransferases, KAT5-KAT8）家族的基因。该家族中包含KAT6A，其突变可引发KAT6A综合征，智力障碍是该病症常见的临床表型。然而，其背后的分子机制目前仍不明确。本研究发现，KAT6A缺失会损伤小鼠海马CA3区的突触结构与突触可塑性，但对CA1区无明显影响，进而导致小鼠出现记忆缺陷。我们进一步鉴定出一种在CA3区富集的基因Rspo2，其编码Wnt激活因子R-spondin 2，是KAT6A的关键转录靶标。值得注意的是，在兴奋性神经元中敲除Rspo2会损害记忆形成，而在Kat6a突变小鼠的CA3区恢复RSPO2的表达，可挽救其Wnt信号通路缺陷与学习相关行为异常。综上，本研究结果表明，KAT6A-RSPO2-Wnt信号通路在调控海马CA3区突触可塑性与认知功能中发挥关键作用，为KAT6A综合征及相关神经发育疾病提供了潜在的治疗靶点。本研究通过Illumina NovaSeq 6000平台开展RNA测序（RNA-seq），获取了成年野生型（wild type）对照与Kat6a+/-小鼠的海马组织mRNA表达谱。