環境溫度調控線蟲壽命的遺傳分析

Abstract

溫度是環境中影響壽命的因素之一。在先前的研究當中發現C. elegans的溫感神經AFD接受環境溫度的刺激並活化DAF-9產生類固醇賀爾蒙，進而延長動物在高溫下的壽命，但是仍然未知的是這些溫度的資訊是如何由神經產生並傳遞的訊息調控由DAF-9所控制的內分泌系統。我們發現在C. elegans中，在溫暖的環境下的壽命需要CREB同源基因crh-1，但是在相對較冷的環境中則不受crh-1的調控。crh-1除了在溫感神經AFD表現之外，同時也在AWC、ASE這兩對感覺神經元以及中間神經元SIA 和腸道細胞中表現。在AFD神經中，溫暖的環境會活化CaMKI/IV 的同源基因CMK-1磷酸化crh-1 並促進動物產生正常的壽命。另外在crh-1 失去活性的動物當中，皮下組織的DAF-9 的表現量明顯的減少，這顯示了 CRH-1藉由DAF-9調控動物的壽命。有趣的是我們發現了FMRFmide-like神經胜肽基因flp-6失去活性的動物表現出類似crh-1 或是cmk-1只在較高的溫度減少壽命的現象。我們證實flp-6和 crh-1作用在同一條途徑上。除此之外， flp-6在AFD神經元當中的表現受到在啟動子中一段由八個核甘酸所組成的 CRE序列調控。另外，在我們初步的結果顯示AFD下游的中間神經元AIY很可能接受由FLP-6所攜帶的訊息進而促進壽命。在本篇研究中，我們發現了一條藉由CREB來整合環境溫度的資訊並且轉化成經由神經胜肽來促進固醇類賀爾蒙的分泌的神經迴路，並且在溫暖環境中促進動物的壽命。

Ambient temperature is one of the diverse environmental stimuli that influence life span. Previous studies indicate that in C. elegans, thermosensory input from the AFD neuron activated the DAF-9 sterol hormone pathway and promoted longevity at warm temperatures. However, how thermosensation is translated into a neuronally derived signal that communicates with the DAF-9 endocrine system remains elusive. We found that crh-1, which encodes the C. elegans CREB, was required for a normal life span at warm, but not at cold temperatures. crh-1 was expressed in the thermosensory neuron AFD, as well as in the AWC, the ASE, the interneuron SIA, and the intestine. crh-1 acted in the AFD for temperature-dependent longevity at warm temperatures, and its activity was dependent on phosphorylation by the CaMKI/IV CMK-1. DAF-9 level was decreased in the hypodermal tissues of the crh-1 mutant, suggesting that DAF-9 mediates the effects of CRH-1 on longevity. Interestingly, we found that mutations in the FMRFmide-like neuropeptide gene flp-6 showed temperature-dependent life span reduction similar to that in the crh-1 or the cmk-1 mutant. We demonstrated that flp-6 acted in a common pathway with crh-1, was expressed in the AFD neuron, and its expression was dependent on a CRE motif in its promoter. Our preliminary results suggested that the interneuron AIY, which does not express CRH-1, may be the downstream cell that FLP-6 targets to regulate longevity. Together these experiments identify a CREB-dependent neuronal circuit that integrates information on ambient temperature into a synaptic neuropeptide signal, which then promotes longevity at warm temperatures by positively regulating the sterol hormone endocrine system.