Retrograde BMP Signaling at the Synapse: A Permissive Signal for Synapse Maturation and Activity-Dependent Plasticity
Retrograde BMP Signaling at the Synapse: A Permissive Signal for Synapse Maturation and Activity-Dependent Plasticity
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DOI：
10.1523/jneurosci.6075-11.2013
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发表时间：
2013-11-06
影响因子：
5.3
通讯作者：
Keshishian, Haig
中科院分区：
文献类型：
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作者：
Berke, Brett;Wittnam, Jessica;Keshishian, Haig
在果蝇神经肌肉接头（NMJ）处，逆行、跨突触BMP信号传导的丧失导致运动神经元末梢的突触终末减少，而神经元活动的增加导致突触更大，突触更多。在这里，我们表明，一个早期和短暂的BMP信号是必要的和足够的NMJ的增长，以及活性依赖性突触可塑性。这一早期的关键时期是由SMAD 1转录调节因子Mad的时间控制抑制所揭示的。通过涉及肌肉中BMP 4/5/6配体玻璃底船（Gbb）和运动神经元中的IIBP型受体Wishful Thinking（Wit）的遗传拯救试验，也发现了类似的结果。这些观察结果支持了一个模型，肌肉信号回到支配运动神经元的核，激活突触前程序突触生长和活动依赖性可塑性所必需的。分子遗传学功能获得和丧失研究表明，参与NMJ生长和可塑性的基因，包括腺苷酸环化酶Rutabaga，Ig-CAM Fasciclin II，转录因子AP-1（Fos/Jun）和粘附蛋白Neurexin，都严重依赖于经典的BMP途径发挥作用。相比之下，Lar（一种被发现对活性依赖性可塑性是必需的受体蛋白酪氨酸磷酸酶）的表达升高，挽救了与Mad信号丢失相关的表型。我们还发现，突触结构和功能的发展使用遗传分离，BMP依赖的机制。虽然突触生长依赖于Lar和早期的瞬时BMP信号，但神经递质释放的成熟不依赖于Lar，而需要后期的持续BMP信号。
At the Drosophila neuromuscular junction (NMJ), the loss of retrograde, trans-synaptic BMP signaling causes motoneuron terminals to have fewer synaptic boutons, whereas increased neuronal activity results in a larger synapse with more boutons. Here, we show that an early and transient BMP signal is necessary and sufficient for NMJ growth as well as for activity-dependent synaptic plasticity. This early critical period was revealed by the temporally controlled suppression of Mad, the SMAD1 transcriptional regulator. Similar results were found by genetic rescue tests involving the BMP4/5/6 ligand Glass bottom boat (Gbb) in muscle, and alternatively the type IIBMPreceptor Wishful Thinking (Wit) in the motoneuron. These observations support a model where the muscle signals back to the innervating motoneuron's nucleus to activate presynaptic programs necessary for synaptic growth and activity-dependent plasticity. Molecular genetic gain-and loss-of-function studies show that genes involved in NMJ growth and plasticity, including the adenylyl cyclase Rutabaga, the Ig-CAM Fasciclin II, the transcription factor AP-1 (Fos/Jun), and the adhesion protein Neurexin, all depend critically on the canonical BMP pathway for their effects. By contrast, elevated expression of Lar, a receptor protein tyrosine phosphatase found to be necessary for activity-dependent plasticity, rescued the phenotypes associated with the loss of Mad signaling. We also find that synaptic structure and function develop using genetically separable, BMP-dependent mechanisms. Although synaptic growth depended on Lar and the early, transientBMPsignal, the maturation of neurotransmitter release was independent of Lar and required later, ongoingBMP signaling.