Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California, United States of America.
PLoS One. 2011 Mar 31;6(3):e18439. doi: 10.1371/journal.pone.0018439.
The neurobiological activities of classical major histocompatibility class I (MHCI) molecules are just beginning to be explored. To further examine MHCI's actions during the formation of neuronal connections, we cultured embryonic mouse retina explants a short distance from wildtype thalamic explants, or thalami from transgenic mice (termed "NSE-Db") whose neurons express higher levels of MHCI. While retina neurites extended to form connections with wildtype thalami, we were surprised to find that retina neurite outgrowth was very stunted in regions proximal to NSE-Db thalamic explants, suggesting that a diffusible factor from these thalami inhibited retina neurite outgrowth. It has been long known that MHCI-expressing cells release soluble forms of MHCI (sMHCI) due to the shedding of intact MHCI molecules, as well as the alternative exon splicing of its heavy chain or the action proteases which cleave off it's transmembrane anchor. We show that the diffusible inhibitory factor from the NSE-Db thalami is sMHCI. We also show that COS cells programmed to express murine MHCI release sMHCI that inhibits neurite outgrowth from nearby neurons in vitro. The neuroinhibitory effect of sMHCI could be blocked by lowering cAMP levels, suggesting that the neuronal MHCI receptor's signaling mechanism involves a cyclic nucleotide-dependent pathway. Our results suggest that MHCI may not only have neurobiological activity in its membrane-bound form, it may also influence local neurons as a soluble molecule. We discuss the involvement of complement proteins in generating sMHCI and new theoretical models of MHCI's biological activities in the nervous system.
经典主要组织相容性复合体 I 类 (MHC I) 分子的神经生物学活性才刚刚开始被探索。为了进一步研究 MHC I 在神经元连接形成过程中的作用，我们在距离野生型丘脑外植体较短的距离培养胚胎小鼠视网膜外植体，或者来自转基因小鼠（称为“NSE-Db”）的丘脑，其神经元表达更高水平的 MHC I。虽然视网膜神经突延伸形成与野生型丘脑的连接，但令我们惊讶的是，在靠近 NSE-Db 丘脑外植体的区域，视网膜神经突的生长非常受阻，这表明这些丘脑的一种扩散因子抑制了视网膜神经突的生长。长期以来，人们一直知道 MHC I 表达细胞由于完整 MHC I 分子的脱落以及其重链的选择性外显子剪接或切割其跨膜锚的蛋白酶的作用而释放可溶性形式的 MHC I (sMHC I)。我们表明，来自 NSE-Db 丘脑的扩散抑制因子是 sMHC I。我们还表明，经编程表达鼠 MHC I 的 COS 细胞释放抑制附近神经元体外神经突生长的 sMHC I。sMHC I 的神经抑制作用可以通过降低 cAMP 水平来阻断，这表明神经元 MHC I 受体的信号转导机制涉及环核苷酸依赖性途径。我们的结果表明，MHC I 不仅在其膜结合形式中具有神经生物学活性，它还可能作为可溶性分子影响局部神经元。我们讨论了补体蛋白在产生 sMHC I 中的作用以及 MHC I 在神经系统中的生物学活性的新理论模型。
