Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115; Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts 02115.
J Biol Chem. 2018 Aug 3;293(31):12026-12042. doi: 10.1074/jbc.RA117.001488. Epub 2018 Jun 18.
Synapse maturation is a neural activity-dependent process during brain development, in which active synapses preferentially undergo maturation to establish efficient neural circuits in the brain. Defects in this process are implicated in various neuropsychiatric disorders. We have previously reported that a postsynaptic transmembrane protein, signal regulatory protein-α (SIRPα), plays an important role in activity-dependently directing synapse maturation. In the presence of synaptic activity, the ectodomain of SIRPα is cleaved and released and then acts as a retrograde signal to induce presynaptic maturation. However, how SIRPα detects synaptic activity to promote its ectodomain cleavage and synapse maturation is unknown. Here, we show that activity-dependent tyrosine phosphorylation of SIRPα is critical for SIRPα cleavage and synapse maturation. We found that during synapse maturation and in response to neural activity, SIRPα is highly phosphorylated on its tyrosine residues in the hippocampus, a structure critical for learning and memory. Tyrosine phosphorylation of SIRPα was necessary for SIRPα cleavage and presynaptic maturation, as indicated by the fact that a phosphorylation-deficient SIRPα variant underwent much less cleavage and could not drive presynaptic maturation. However, SIRPα phosphorylation did not affect its synaptic localization. Finally, we show that inhibitors of the Src and JAK kinase family suppress neural activity-dependent SIRPα phosphorylation and cleavage. Together, our results indicate that SIRPα phosphorylation serves as a mechanism for detecting synaptic activity and linking it to the ectodomain cleavage of SIRPα, which in turn drives synapse maturation in an activity-dependent manner.
突触成熟是大脑发育过程中一种依赖于神经活动的过程，在此过程中，活跃的突触优先经历成熟，从而在大脑中建立有效的神经回路。这一过程的缺陷与各种神经精神疾病有关。我们之前曾报道过，一种突触后跨膜蛋白信号调节蛋白-α（SIRPα）在活动依赖性指导突触成熟中发挥着重要作用。在突触活动存在的情况下，SIRPα 的胞外结构域被切割并释放，然后作为逆行信号诱导突触前成熟。然而，SIRPα 如何检测突触活动以促进其胞外结构域切割和突触成熟尚不清楚。在这里，我们表明 SIRPα 的活性依赖性酪氨酸磷酸化对于 SIRPα 的切割和突触成熟是至关重要的。我们发现，在突触成熟过程中和响应神经活动时，SIRPα 在其酪氨酸残基上高度磷酸化，而这些酪氨酸残基位于海马体中，海马体对于学习和记忆至关重要。SIRPα 的酪氨酸磷酸化对于 SIRPα 的切割和突触前成熟是必需的，这是因为一个磷酸化缺陷的 SIRPα 变体经历的切割要少得多，并且不能驱动突触前成熟。然而，SIRPα 的磷酸化并不影响其突触定位。最后，我们表明 Src 和 JAK 激酶家族的抑制剂可抑制神经活动依赖性 SIRPα 磷酸化和切割。总之，我们的结果表明 SIRPα 磷酸化可作为检测突触活动并将其与 SIRPα 胞外结构域切割联系起来的一种机制，从而以活动依赖性的方式驱动突触成熟。
