Jin Jinpu, Ralls Sherry, Wu Elaine, Wolf Gernot, Sun Ming-An, Springer Danielle A, Cosby Rachel L, Senft Anna D, Macfarlan Todd S
The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu 225009, China.
bioRxiv. 2023 May 8:2023.05.08.539838. doi: 10.1101/2023.05.08.539838.
Mammalian brains are larger and more densely packed with neurons than reptiles, but the genetic mechanisms underlying the increased connection complexity amongst neurons are unclear. The expression diversity of clustered protocadherins (Pcdhs), which is controlled by CTCF and cohesin, is crucial for proper dendritic arborization and cortical connectivity in vertebrates. Here, we identify a highly-conserved and mammalian-restricted protein, ZFP661, that binds antagonistically at CTCF barriers at the locus, preventing CTCF from trapping cohesin. ZFP661 balances the usage of Pcdh isoforms and increases Pcdh expression diversity. Loss of causes cortical dendritic arborization defects and autism-like social deficits in mice. Our study reveals both a novel mechanism that regulates the trapping of cohesin by CTCF and a mammalian adaptation that promoted Pcdh expression diversity to accompany the expanded mammalian brain.
哺乳动物的大脑比爬行动物更大，神经元分布更密集，但神经元之间连接复杂性增加背后的遗传机制尚不清楚。由CTCF和黏连蛋白控制的成簇原钙黏蛋白（Pcdhs）的表达多样性，对于脊椎动物正确的树突分支和皮质连接至关重要。在这里，我们鉴定出一种高度保守且仅限于哺乳动物的蛋白质ZFP661，它在该位点的CTCF屏障处拮抗结合，阻止CTCF捕获黏连蛋白。ZFP661平衡了Pcdh异构体的使用并增加了Pcdh表达多样性。ZFP661缺失会导致小鼠出现皮质树突分支缺陷和自闭症样社交缺陷。我们的研究揭示了一种调节CTCF捕获黏连蛋白的新机制，以及一种促进Pcdh表达多样性以适应哺乳动物大脑扩张的哺乳动物适应性变化。
