Background Transcription factor 4 ( TCF4 ) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life. Results We here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice. Conclusion The present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

中文翻译：

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丰富的环境改善了 Tcf4 单倍体不足小鼠的成年海马神经发生缺陷

背景 转录因子 4 (TCF4) 与人类神经发育障碍有关，例如智力障碍、皮特霍普金斯综合征 (PTHS)、自闭症和精神分裂症。最近的工作表明，TCF4 参与控制哺乳动物神经系统发育中广泛的神经发育过程，包括神经前体增殖、分化时间、迁移、树突生成和突触形成。TCF4 在成年海马齿状回中高度表达，这是神经干/祖细胞在整个生命过程中产生新的功能性神经元的少数大脑区域之一。结果 我们在此调查了 TCF4 单倍体不足（在人类中导致非综合征形式的智力障碍和 PTHS）是否影响成人海马神经发生，这一过程对于啮齿类动物和潜在的人类海马体的可塑性至关重要。年轻的成年 Tcf4 杂合子敲除小鼠表现出成年海马神经发生水平的显着降低，这至少部分是由较低的干/祖细胞数量和成年生成神经元的成熟和存活受损引起的。有趣的是，居住在丰富的环境中足以增强新神经元的成熟和存活，并大大增加 Tcf4 杂合子敲除小鼠的神经发生水平。结论 目前的研究结果表明，智力障碍和 PTHS 相关转录因子 TCF4 的单倍体不足不仅影响胚胎神经发育，而且阻碍成年小鼠海马体的神经发生。