Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology.
Activating transcription factor 4 (ATF4) modulates post-synaptic development and dendritic spine morphology.
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DOI：
10.3389/fncel.2014.00177
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发表时间：
2014
影响因子：
5.3
通讯作者：
Greene LA
中科院分区：
文献类型：
--
作者：
Liu J;Pasini S;Shelanski ML;Greene LA
激活转录因子4(ATF4)广泛表达，对神经元的可塑性和记忆有促进或抑制作用。然而，ATF4在大脑中的这些和其他作用的潜在细胞基础还不是很清楚。在这篇报道中，我们重点研究了血管紧张素转换酶4的S在突触后突触发育和树突棘形态中的作用。ShRNA介导的ATF4沉默显著降低了长期培养的皮质和海马神经元中PSD-95和GluR1斑点(可能是兴奋性突触的标记)的密度。ATF4基因敲除也降低了蘑菇刺的密度，并增加了这种培养物中异常长的树状丝状足的形成。在体内，敲除成年小鼠海马神经元中的ATF4也降低了蘑菇刺的密度。相反，ATF4过表达并不影响PSD-95点刺或蘑菇刺的密度。ATF4对突触点状突触和棘突密度的调节需要其转录活性，至少部分是通过间接控制肌动蛋白调节蛋白CDC42的稳定性和表达来实现的。为了支持这一机制，ATF4沉默使培养的大脑皮层神经元中CDC42的半衰期从31.5小时减少到18.5小时，而与ATF4基因敲除一样，CDC42的敲除也减少了蘑菇刺和PSD-95点的密度。因此，ATF4似乎通过调控突触和树突状蘑菇棘的突触后发育来参与神经元的发育和可塑性，其中包括对CDC42水平的调节。
The ubiquitously expressed activating transcription factor 4 (ATF4) has been variably reported to either promote or inhibit neuronal plasticity and memory. However, the potential cellular bases for these and other actions of ATF4 in brain are not well-defined. In this report, we focus on ATF4's role in post-synaptic synapse development and dendritic spine morphology. shRNA-mediated silencing of ATF4 significantly reduces the densities of PSD-95 and GluR1 puncta (presumed markers of excitatory synapses) in long-term cultures of cortical and hippocampal neurons. ATF4 knockdown also decreases the density of mushroom spines and increases formation of abnormally-long dendritic filopodia in such cultures. In vivo knockdown of ATF4 in adult mouse hippocampal neurons also reduces mushroom spine density. In contrast, ATF4 over-expression does not affect the densities of PSD-95 puncta or mushrooom spines. Regulation of synaptic puncta and spine densities by ATF4 requires its transcriptional activity and is mediated at least in part by indirectly controlling the stability and expression of the total and active forms of the actin regulatory protein Cdc42. In support of such a mechanism, ATF4 silencing decreases the half-life of Cdc42 in cultured cortical neurons from 31.5 to 18.5 h while knockdown of Cdc42, like ATF4 knockdown, reduces the densities of mushroom spines and PSD-95 puncta. Thus, ATF4 appears to participate in neuronal development and plasticity by regulating the post-synaptic development of synapses and dendritic mushroom spines via a mechanism that includes regulation of Cdc42 levels.
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