環境溫度透過神經胜肽調控線蟲壽命的機制

Abstract

溫度是已知影響壽命的重要環境因素之一。之前的研究指出，在線蟲C. elegans，由溫感神經元AFD及中間神經元AIY所組成的溫感神經迴路調控了線蟲在高溫環境下的壽命，但是由溫感神經迴路所傳遞的神經訊息如何調控線蟲的整體壽命仍然未知。我們發現CREB的同源轉錄因子crh-1及神經胜肽flp-6在高溫下對於線蟲維持正常壽命是必要的。在溫感神經元AFD中，溫度的上升會透過磷酸化轉化為crh-1的活性，活化的CRH-1會進而提高flp-6的表現量。我們認為flp-6可能是藉由直接作用在中間神經元AIY上來調控壽命。我們也發現crh-1不是透過熱休克反應，而是藉由胰島素訊息路徑來調控壽命。我們發現crh-1、flp-6及daf-16皆作用在相同的路徑上，從比較野生型及flp-6突變的線蟲基因表現，我們發現了幾個參與在胰島素訊息路徑中的基因，其表現量在flp-6突變株中有明顯的上升，例如類胰島素胜肽ins-7。ins-7在腸道的表現量會受到crh-1及flp-6抑制，去除ins-7可延長flp-6突變線蟲在高溫下的短壽命。總結以上結果，我們發現溫感神經迴路感受到環境溫度的上升後，藉由溫感神經迴路所傳遞的神經胜肽flp-6訊息抑制了線蟲體內的類胰島素胜肽ins-7的活性，來維持線蟲在高溫下的壽命。

Temperature is an important environmental cue that influences longevity. In the nematode Caenorhabditis elegans, the thermosensory neuronal circuit, including the thermosensory neuron AFD and the interneuron AIY, is required for normal life span at warm temperatures, but how thermosensory perception control temperature-specific longevity response remains elusive. We found that CRH-1, the C. elegans cyclic AMP response element binding protein, and the FMRFamide-like neuropeptide FLP-6 acted in the AFD, and that both crh-1 and flp-6 were necessary and sufficient for longevity control in a temperature-dependent manner, with flp-6 acting downstream of crh-1. crh-1 transcriptionally upregulated flp-6. In a CRE- (cyclic AMP response element) and temperature-dependent manner. Our data suggested that flp-6 may target the AIY in longevity regulation. The effects of crh-1 on longevity were independent of the heat shock response pathway, but may engage insulin signaling, as genetic analysis of longevity phenotypes in crh-1, flp-6 and daf-16 mutants suggested that they functioned in a common pathway. This was supported by our profiling of the flp-6 mutant transcriptome compared to that of the wild type, which identified several insulin pathway genes being upregulated in the flp-6 mutant, including the insulin-like peptide (ILP) ins-7. crh-1 and flp-6 negatively regulated ins-7 expression in the intestine, and the ins-7 mutation completely suppressed longevity deficits of the flp-6 mutant at warm temperature. Together these experiments identify an flp-6/FLP-to-ins-7/ILP neuropeptide signaling circuit as an output from the thermosensory neuron for longevity control in response to a rise in the ambient temperature.