German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilian-University, Munich, Germany.
PLoS One. 2018 Jun 22;13(6):e0199359. doi: 10.1371/journal.pone.0199359. eCollection 2018.
Tcf4 is a transcription factor which regulates neurogenesis and neuronal migration in the brain. In humans, loss of function of Tcf4 leads to the rare neurodevelopmental disorder Pitt-Hopkins syndrome, which is characterized by intellectual disability, developmental delay and autistic behavior. We analyzed the consequences of functional loss of Tcf4 on dendritic spines in mature principal neurons. To this end, we crossed mice in which the DNA-binding domain of the Tcf4 gene is flanked by LoxP sites to mice expressing tamoxifen-inducible cre recombinase in a sparse subset of fluorescently labelled neurons (SlickV line). This resulted in a mouse model with an inducible functional knockout of Tcf4 in a subset of cortical and hippocampal neurons, in which we analyzed dendritic spines, which are the morphological correlate of excitatory postsynapses. Heterozygous as well as homozygous loss of Tcf4 led to a reduction in the number of dendritic spines in the cortex as well as in the hippocampus. This was accompanied by morphological changes of dendritic spines. These results suggest that Tcf4 is involved in synaptic plasticity in mature neurons, and functional loss of Tcf4 may contribute to the neurological symptoms in Pitt-Hopkins syndrome.
Tcf4 是一种转录因子，它调节大脑中的神经发生和神经元迁移。在人类中，Tcf4 的功能丧失会导致罕见的神经发育障碍——皮特 - 霍普金斯综合征，其特征为智力残疾、发育迟缓以及自闭症行为。我们分析了 Tcf4 功能丧失对成熟主神经元树突棘的影响。为此，我们将 Tcf4 基因的 DNA 结合域被 LoxP 位点包围的小鼠与在稀疏的荧光标记神经元（SlickV 系）中表达他莫昔芬诱导型 cre 重组酶的小鼠进行杂交。这导致了一种在皮质和海马神经元亚群中可诱导的 Tcf4 功能缺失的小鼠模型，我们在此模型中分析了树突棘，它是兴奋性突触后相关的形态学特征。杂合子和纯合子缺失 Tcf4 导致皮质和海马中树突棘数量减少。这伴随着树突棘的形态变化。这些结果表明，Tcf4 参与成熟神经元中的突触可塑性，Tcf4 的功能丧失可能导致皮特 - 霍普金斯综合征的神经症状。
