2. 青岛海洋科学与技术试点国家实验室海洋渔业科学与食物产出过程功能实验室 青岛 266071;
3. 上海海洋大学水产与生命学院 上海 201306
2. Laboratory for Marine Fisheries and Food Production Processes, Pilot National Laboratory for Marine Science and Technology(Qingdao), Qingdao 266071;
3. College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306
下丘脑神经肽kisspeptin及其受体KissR在哺乳动物生殖调控及青春期启动中发挥了重要作用(Roa et al, 2011; Tena-Sempere, 2010)。迄今，除鸟类外，在其他脊椎动物中均鉴定出了kiss基因。除鸭嘴兽(Ornithorhynchus anatinus)外，哺乳类只存在Kiss1基因；两栖类存在kiss1a、kiss1b及kiss2三种基因；爬行类只存在kiss2基因；斑马鱼(Danio rerio)、青鳉(Oryzias latipes)、金鱼(Carassius auratus)、欧洲海鲈(Dicentrarchus labrax)、条纹鲈(Morone saxatilis)及鲐鱼(Scomber japonicus)中存在kiss1和kiss2两种基因。相反，在尼罗罗非鱼(Oreochromis niloticus)、斜带石斑鱼(Epinephelus coioides)、塞内加尔鳎(Solea senegalensis)、半滑舌鳎(Cynoglossus semilaevis)以及星点东方鲀(Takifugu niphobles)中只鉴定出了kiss2基因(Pasquier et al, 2014; Um et al, 2010; Wang et al, 2017b)。目前，已在多种鱼类中鉴定出了Kiss系统，其在鱼类生殖调控中的生理功能研究也日益完善(Akazome et al, 2010; Mechaly et al, 2013; Tena-Sempere et al, 2012)。本文简要总结鱼类Kiss及其受体的研究进展，并对Kiss的生理学功能、信号转导机制以及kiss/kissr表达调控研究进行概括讨论，旨在加深对鱼类Kiss/KissR系统的认识和了解，为后续研究奠定基础。
1 Kisspeptin的发现及与生殖的关系KISS1基因最初是从人(Homo sapiens)黑色素瘤和乳腺癌细胞中分离得到的，因其具有抑制肿瘤生长和转移的功能，Kiss最初被命名为转移抑制素(Metastin) (Lee et al, 1996、1997)。Lee等(1999)从大鼠(Rattus norvegicus)脑中鉴定出了1种新型G蛋白偶联受体，命名为GPR54。2年后，Kiss被认为是孤儿受体GPR54的内源性配体(Kotani et al, 2001; Muir et al, 2001; Ohtaki et al, 2001)。2003年，2个独立研究组发现，突变GPR54导致人特发性性腺功能减退(de Roux et al, 2003; Seminara et al, 2003)。随后研究发现，基因敲除KISS1或者GPR54均影响性腺发育及生殖功能(d′Anglemont de Tassigny et al, 2007; Seminara et al, 2003)，说明Kiss/GPR54系统在哺乳类生殖调控中发挥了关键作用。
近几年，kisspeptin在鱼类生殖调控中的作用也有较多研究。如Kiss1直接促进了金鱼垂体细胞黄体生成素(Luteinizing hormone, LH)分泌(Chang et al, 2012; Yang et al, 2010)。Kiss2也促进了欧洲海鲈(Espigares et al, 2015b)和条纹鲈(Zmora et al, 2015)垂体细胞LH及卵泡刺激素(Follicle-stimulating hormone, FSH)分泌。此外，Kiss1增加了金鱼垂体细胞lhβ的表达水平(Yang et al, 2010)。然而，Kiss1特异性地降低了欧洲鳗鲡垂体细胞lhβ的表达水平(Pasquier et al, 2011)。腹腔注射Kiss2促进了斑马鱼垂体lhβ及fshβ的表达水平(Kitahashi et al, 2009)，而Kiss2特异性地促进了斜带石斑鱼垂体fshβ的表达量，对lhβ的表达水平无影响(Shi et al, 2010)。综上所述，kisspeptin参与了鱼类生殖调控，但具体作用机制因物种而异。
2 鱼类kiss基因类型、结构及时空表达特性由于KISS1/Kiss1基因不是很保守，直到2008年才在非哺乳类中鉴定出了其同源基因。van Aerle等(2008)利用全基因组序列及比较共线性方法，首次在斑马鱼和青鳉等5种鱼类中鉴定出了kiss1基因。随后，Biran等(2008)和Kanda等(2008)也通过类似方法，分别在斑马鱼和青鳉中获得了kiss1基因。2009年，kiss2基因首次在斑马鱼、青鳉和欧洲海鲈中被鉴定出来(Felip et al, 2009; Kitahashi et al, 2009)。斑马鱼kiss1基因编码116个氨基酸的前体多肽，其C末端核心十肽为YNLNSFGLRY (Y-Y形式) (Biran et al, 2008; van Aerle et al, 2008)；斑马鱼kiss2基因编码125个氨基酸的前体多肽，其C末端核心十肽为FNYNPFGLRF (F-F形式) (Kitahashi et al, 2009)。与之类似，其他鱼类C末端十肽序列与斑马鱼高度保守，该十肽也是发挥其功能所需的最短序列(Akazome et al, 2010; Pasquier et al, 2014)。在哺乳类中，KISS1/Kiss1基因由3个外显子和2个内含子组成，其中，外显子1只编码一部分5′UTR，外显子2编码另一部分5′UTR及一部分CDS，剩余另一部分CDS及3′UTR由外显子3编码(Pasquier et al, 2014)。同样，斑马鱼kiss1基因也是由3个外显子和2个内含子组成，而kiss2基因由2个外显子和1个内含子组成(Kitahashi et al, 2009)。塞内加尔鳎kiss2基因也是由2个外显子和1个内含子组成，但是，其存在2种剪接变异体：较短亚型kiss2_v1编码正常Kiss2前体多肽；较长亚型kiss2_v1编码一种缩短形式的无功能多肽(Mechaly et al, 2011)。
鱼类kiss1及kiss2的组织分布因物种而异，即使同一物种不同脑区表达也有所差异。斑马鱼kiss1主要在间脑和中脑中表达，其次为后脑，在端脑和垂体中表达量较低(Biran et al, 2008)；在外周组织中，斑马鱼kiss1在胰腺和前肠中表达量较高，其次为性腺(Biran et al, 2008)。与之类似，青鳉(Felip et al, 2009; Kitahashi et al, 2009)、欧洲海鲈(Felip et al, 2009)、金鱼(Li et al, 2009; Yang et al, 2010)、鲐鱼(Shahjahan et al, 2010)等脑和性腺中kiss1表达量也较高。kiss2也主要在脑和性腺中高表达，如斑马鱼(Kitahashi et al, 2009)、青鳉(Kitahashi et al, 2009)、金鱼(Li et al, 2009)、欧洲海鲈(Felip et al, 2009)、塞内加尔鳎(Mechaly et al, 2011)及南亚黑鲮(Labeo rohita) (Saha et al, 2016)等。此外，kiss2也在肠、肾脏、心脏等其他外周组织有所表达，具体表达模式具有物种特异性。
鱼类kiss基因在不同发育阶段/生殖周期的表达模式也在斑马鱼等几种鱼类中有所报道。雌性斑马鱼脑kiss1表达量在孵化后逐渐升高，84 d时达到峰值；而雄性斑马鱼脑kiss1表达量在孵化后6周达到峰值，12周时有所下降(Biran et al, 2008)。此外，斑马鱼kiss2表达量在孵化后30 d达到峰值(Kitahashi et al, 2009)。上述结果显示，kiss可能参与了斑马鱼青春期启动。鲐鱼脑kiss在不同生殖周期的表达模式具有性别二态性，雄性脑kiss1表达量随精巢发育逐渐降低，而雌性脑kiss1表达量在卵巢发育过程中保持不变；除了分别在卵黄生成早期和精子生成晚期略微增加外，雌雄脑kiss2表达量随性腺发育逐渐降低，均在产卵/排精后达到最小值(Selvaraj et al, 2010)。然而，精巢kiss1表达水平随性腺发育逐渐升高，在精子成熟时期达到峰值；卵巢kiss1表达水平也随性腺发育逐渐升高，在卵黄生成后期达到峰值(Selvaraj et al, 2010)。以上结果表明，kiss可能参与了鲐鱼季节性性腺发育。其他鱼类kiss表达水平也随性腺发育而发生波动(Alvarado et al, 2013; Migaud et al, 2012; Park et al, 2016; Saha et al, 2016; Shahi et al, 2017)。
3 鱼类kissr基因类型、结构及时空表达特性Parhar等(2004)首次在罗非鱼中鉴定出了GPR54的同源基因(kiss2r)，随后在鲻鱼(Mugil cephalus) (Nocillado et al, 2007)、军曹鱼(Rachycentron canadum) (Mohamed et al, 2007)、斑马鱼(Biran et al, 2008; van Aerle et al, 2008)、黑头呆鱼(Pimephales promelas) (Filby et al, 2008)、塞内加尔鳎(Mechaly et al, 2009)、大西洋庸鲽(Hippoglossus hippoglossus) (Mechaly et al, 2010)、斜带石斑鱼(Shi et al, 2010)及星点东方鲀(Shahjahan et al, 2010)中也鉴定出了kiss2r基因。另外，kiss1r基因也在斑马鱼(Biran et al, 2008)、青鳉(Lee et al, 2009)及金鱼(Li et al, 2009)中被鉴定出来。同kiss2基因类似，迄今在所有研究的鱼类中都存在kiss2r基因，表明kiss2/kiss2r系统在进化过程中高度保守。欧洲鳗鲡(Anguilla anguilla)是目前唯一拥有3种kissr基因的硬骨鱼类(Pasquier et al, 2012)。在哺乳类中，Kiss1R基因由5个外显子和4个内含子组成，而青鳉和欧洲海鲈kiss1r基因均由6个外显子和5个内含子组成(Tena-Sempere et al, 2012)。塞内加尔鳎kiss2r基因由5个外显子和4个内含子组成(Mechaly et al, 2009)。有些鱼类kissr有多种剪接异构体，如塞内加尔鳎(2种kiss2r亚型) (Mechaly et al, 2009)、黄条
在鱼类中，kiss1r及kiss2r的组织分布因物种而异。斑马鱼kiss1r主要在脑和垂体中表达，在肠、肾脏、胰腺及脂肪组织中也有所表达(Biran et al, 2008)。鲐鱼kiss1r的表达模式具有性别二态性，雄性kiss1r的表达量在脑中最高，其次为脾脏、性腺及心脏，但在垂体中不表达；雌性kiss1r主要在脑中表达，在鳃、心脏、胰腺及脾脏等组织中表达量较低，在垂体中不表达(Ohga et al, 2013)。金鱼kiss2r主要在脑中表达，在性腺和脂肪组织中也有表达(Li et al, 2009)；欧洲鳗鲡kiss2r主要在脑和垂体中表达，但在肝脏和脂肪组织中不表达(Pasquier et al, 2011)。然而，kiss2r只在裸盖鱼(Anoplopoma fimbria)脑中表达(Fairgrieve et al, 2016)。总体来说，kiss2r在黑头呆鱼(Filby et al, 2008)、斑马鱼(Biran et al, 2008; van Aerle et al, 2008)、塞内加尔鳎(Mechaly et al, 2009)、星点东方鲀(Shahjahan et al, 2010)、蓝鳍金枪鱼(Nocillado et al, 2012)、黄条
通常，哺乳类下丘脑Kiss1R的表达水平在青春期显著性增加(Dungan et al, 2006)。鱼类kissr的表达模式也与生殖周期有关。鲻鱼脑kiss2r的表达水平随性腺发育而降低，在青春期前期表达量最高(Nocillado et al, 2007)。与之类似，军曹鱼、黑头呆鱼及大西洋庸鲽脑kiss2r的表达量也均在青春期达到峰值(Filby et al, 2008; Mechaly et al, 2010; Mohamed et al, 2007)。斑马鱼脑kiss2r的表达量在孵化后8周时显著性增加，随后回到本底水平；而kiss1r的表达量在孵化后6周时显著增加，随后一直保持到12周(Biran et al, 2008)。鲐鱼脑kissr在不同生殖周期的表达模式具有性别二态性，雄鱼脑kiss1r及kiss2r的表达水平不随精巢发育过程而变化；而雌鱼脑kiss1r及kiss2r的表达水平均在卵黄生成早期显著增加并达到峰值，继而随卵巢发育过程又回到本底水平(Ohga et al, 2013)。精巢kiss1r表达水平随性腺发育逐渐升高，在精子成熟时期达到峰值；而精巢kiss2r表达水平不随性腺发育过程而变化(Ohga et al, 2013)。综上所述，kissr可能参与了鱼类青春期启动及季节性性腺发育。
4 Kisspeptin对鱼类生殖调控作用研究 4.1 Kisspeptin对下丘脑促性腺激素释放激素(Gonadotropin-releasing hormone, GnRH)神经元活性以及表达调控的影响GnRH是垂体促性腺激素合成与分泌的主要促进因子，在每种硬骨鱼类中存在至少2种GnRH多肽(Zohar et al, 2010; 王滨等, 2017)。Parhar等(2004)首次在罗非鱼中鉴定出了kiss2r基因，并进一步证实kiss2r在GnRH1、GnRH2及GnRH3神经元中表达，这表明Kiss2能够直接作用于GnRH神经元，进而影响其活性及表达调控。在青鳉中，通过电生理学研究表明，Kiss1能够促进GnRH3神经元的电活动(Electrical activity)，而河豚毒素或者阻断突触传递均降低了Kiss1诱导的GnRH3神经元的电活动，这表明Kiss1以间接方式通过突触调控进而激活GnRH3神经元的电活动(Zhao et al, 2012)。
由于鱼类存在多种kiss及gnrh基因，导致Kiss多肽对gnrh的表达调控更具复杂性。腹腔/肌肉注射Kiss1和Kiss2均不影响斑马鱼和杂交条纹鲈(M. saxatilis × M. chrysops)脑gnrh2以及gnrh3的表达水平(Kitahashi et al, 2009; Zmora et al, 2012)。同样，Kiss2也不影响半滑舌鳎离体孵育下丘脑中gnrh2以及gnrh3的表达水平(Wang et al, 2017a)。腹腔注射Kiss1不影响黑头呆鱼脑gnrh2的表达水平，却促进了gnrh3的表达水平(Filby et al, 2008)。而腹腔注射Kiss2不影响斜带石斑鱼下丘脑gnrh3的表达水平，却促进了gnrh1的表达水平(Shi et al, 2010)。同样，腹腔注射Kiss2也促进了尼罗罗非鱼脑gnrh1的表达水平(Park et al, 2016)。相反，侧脑室注射Kiss1和Kiss2均降低了欧洲海鲈前中脑gnrh1和gnrh2的表达水平，对前中脑gnrh3及下丘脑gnrh1的表达水平无影响(Espigares et al, 2015a)。埋植Kiss1和Kiss2均不影响黄条
腹腔注射Kiss1不影响斑马鱼垂体生长激素(Growth hormone)gh、lhβ及fshβ的表达水平(Kitahashi et al, 2009)。皮下及侧脑室注射Kiss1也均不影响鲐鱼垂体lhβ及fshβ的表达水平(Ohga et al, 2014; Selvaraj et al, 2013b)。Kiss1特异性地降低了欧洲鳗鲡垂体细胞lhβ的表达水平，对gh、gthα、fshβ及tshβ的表达量无影响(Pasquier et al, 2011)。相反，Kiss1增加了金鱼垂体细胞gh、lhβ及prl的表达水平(Yang et al, 2010)。长期埋植Kiss1，只促进了非生殖季黄条
由于鱼类中存在2种Kiss多肽，Kiss对鱼类垂体激素分泌的影响更加复杂。肌肉注射Kiss1和Kiss2均提高了青春期前的欧洲海鲈血清LH水平(Felip et al, 2009)；腹腔注射Kiss1而非Kiss2也提高了性成熟雌性金鱼血清LH水平(Li et al, 2009)。但Kiss1和Kiss2均不影响金鱼垂体细胞LH分泌(Li et al, 2009)。相反，另有研究表明，Kiss1直接促进了金鱼垂体细胞LH分泌(Chang et al, 2012; Yang et al, 2010)。最近研究报道，Kiss2而非Kiss1促进了欧洲海鲈(Espigares et al, 2015b)和条纹鲈(Zmora et al, 2015)垂体细胞LH分泌。Kiss1和Kiss2对杂交条纹鲈LH分泌的调控作用与生殖周期相关。在青春前期，肌肉注射Kiss2而非Kiss1增加了血清中LH水平；在性腺复苏期，Kiss1和Kiss2均增加了血清中LH水平(Zmora et al, 2012)。关于FSH分泌调控，肌肉注射Kiss2提高了青春期前的欧洲海鲈血清FSH水平，但是，Kiss1无影响(Felip et al, 2009)。同样，Kiss2而非Kiss1促进了欧洲海鲈垂体细胞FSH分泌(Espigares et al, 2015b)。此外，Kiss1和Kiss2均促进了条纹鲈垂体细胞FSH分泌(Zmora et al, 2015)。而长期埋植Kiss2显著性地降低了条纹鲈血清FSH水平(Zmora et al, 2014)。在鱼类中，关于Kiss对GH分泌的影响仅见于金鱼，Kiss1促进了金鱼垂体细胞GH分泌(Chang et al, 2012; Yang et al, 2010)。综上所述，Kiss对垂体激素分泌的调控作用因物种、生殖周期和注射途径而异，甚至在同一物种的不同生殖周期Kiss1和Kiss2可能发挥了不同的作用。
4.3 Kisspeptin对性腺发育及类固醇激素分泌的影响除了作用于下丘脑和垂体外，Kiss也能够直接作用于性腺，从而影响其发育及类固醇激素的分泌，进而影响生殖调控。最初，Elizur等(2011)通过长期埋植研究表明，Kiss1和Kiss2均能促进青春前期的黄条
众所周知，E2(17β-estradiol)和11-KT(11-ketotes-tosterone)分别是参与卵巢和精巢发育的雌雄类固醇激素，其分泌主要受到垂体LH及FSH调控。在鱼类中研究表明，Kiss通过影响性类固醇激素分泌进而影响性腺发育。皮下埋植Kiss1分别增加了雌雄鲐鱼血清E2及11-KT的水平(Selvaraj et al, 2013a)。腹腔注射Kiss2也分别增加了雌雄罗非鱼血清E2及11-KT的水平(Park et al, 2016)。然而，埋植Kiss1和Kiss2均不影响黄条
在哺乳类中，Kiss能够激活多种细胞内信号通路，例如PLC/IP3/PKC、MAPK以及Ca2+通路等(Castano et al, 2009; Pasquier et al, 2014)，而非哺乳类中有关Kiss信号转导机制的研究相对较少。在两栖类中，Moon等(2009)通过CRE-luc(对应AC/PKA通路)和SRE-luc(对应PLC/PKC通路)报告系统表明，Kiss能够激活转染了牛蛙(Rana catesbeiana) Kiss2R的非洲绿猴肾纤维细胞系(CV-1 cells)中SRE-luc的活性，但对CRE-luc活性无影响。此外，PKC抑制剂GF109203X预处理CV-1细胞系显著性地降低了Kiss诱导的SRE-luc的活性，而Rho激酶抑制剂Y-27632预处理CV-1细胞系部分阻断了Kiss诱导的SRE-luc的活性，上述结果显示，牛蛙Kiss2R可能主要与PKC通路偶联，部分与Rho激酶通路偶联(Moon et al, 2009)。同样，非洲爪蟾(Xenopus laevis) 3种KissR也都与PKC通路偶联(Lee et al, 2009)。
在鱼类中，由于存在2种Kiss及3种KissR，且不同配体与受体之间能够互作，导致其信号转导机制更加复杂。斜带石斑鱼中只存在Kiss2/Kiss2R系统，Kiss2能够激活转染了石斑鱼Kiss2R的COS-7细胞系中SRE-luc的活性，但是，对CRE-luc活性无影响(Shi et al, 2010)。同样，斑马鱼Kiss2R也只与PKC通路偶联，而Kiss1R均与PKC和PKA通路偶联(Biran et al, 2008)。相反，鲐鱼Kiss1R只与PKC通路偶联，而Kiss2R均与PKC和PKA通路偶联(Ohga et al, 2013)。尽管蓝鳍金枪鱼、黄条
性类固醇激素是影响kiss基因表达的主要调控因子之一，其对kiss基因的不同调控(上调/下调)完美解释了性类固醇激素对生殖调控的正负反馈机制，这也是生殖神经内分泌领域研究的一大进展(Kitahashi et al, 2013)。在青鳉中，卵巢切除后，导致其下丘脑核腹侧结节(Nucleus ventral tuberis, NVT)中Kiss1神经元的数量显著性降低，而E2处理后，NVT中Kiss1神经元的数量又回到本底水平，这表明NVT中Kiss1神经元可能参与了生殖轴的正反馈调控(Kanda et al, 2008)。进一步研究表明，青鳉Kiss1神经元中表达E2受体，然而Kiss2神经元中不表达E2受体，且卵巢切除后不影响Kiss2神经元的数量，这表明Kiss1而非Kiss2直接参与了青鳉生殖调控(Mitani et al, 2010)。相反，卵巢切除后，只降低了金鱼下丘脑视前区(Preoptic area, POA)中Kiss2神经元的数量，而E2处理后POA中，Kiss2神经元的数量又回到本底水平，并且，只有Kiss2神经元中表达E2受体，这表明Kiss2而非Kiss1，直接参与了金鱼生殖调控(Kanda et al, 2012)。E2促进了斑马鱼脑kiss2、kiss2r及kiss1的表达水平，对kiss1r的表达水平无影响(Servili et al, 2011)。与之类似，E2也促进了蓝刻齿雀鲷(Chrysiptera cyanea)脑和欧洲海鲈垂体细胞kiss1r及kiss2r的表达水平(Espigares et al, 2015b; Imamura et al, 2016)。然而，用E2处理卵巢切除后的欧洲海鲈，却不影响其下丘脑中kiss1、kiss2、kiss1r及kiss2r的表达水平(Alvarado et al, 2016)。同样，E2也不影响半滑舌鳎下丘脑中kiss2及kiss2r的表达水平(Wang et al, 2017b)。根据浓度及处理时间的不同，EE2(17α-ethinylestradiol)促进或者抑制了稀有
Kiss/KissR系统也介导了睾酮(Testosterone, T)对生殖轴的反馈调控。一方面，用睾酮处理卵巢切除后的雌性条纹鲈，降低了其脑中kiss1、kiss2及kiss2r的表达水平(Klenke et al, 2011)。另一方面，用睾酮处理精巢切除后的雄性欧洲海鲈，降低了其下丘脑中kiss2的表达水平，却不影响kiss1、kiss1r及kiss2r的表达水平(Alvarado et al, 2016)。然而，睾酮促进了雄性欧洲海鲈垂体细胞kiss1r及kiss2r的表达水平，对kiss2的表达水平无影响(Espigares et al, 2015b)。此外，睾酮也不影响半滑舌鳎下丘脑中kiss2及kiss2r的表达水平(Wang et al, 2017b)。目前，关于甲状腺激素(Thyroid hormone)对鱼类kiss/kissr系统的调控作用仅见于罗非鱼。腹腔注射甲状腺激素，显著地增加了罗非鱼脑kiss2的表达水平，但由于甲状腺激素受体不在Kiss2神经元中表达，这表明甲状腺激素是以间接的方式影响kiss2的表达(Ogawa et al, 2013)。综上所述，性类固醇激素及甲状腺激素通过影响kiss/kissr系统的表达水平进而影响鱼类生殖调控。
6.2 Kisspeptin等神经肽对kiss/kissr系统的调控作用在鱼类中，Kiss对kiss/kissr系统的自分泌调控也进行了研究。颅腔注射Kiss1抑制了斑马鱼松果体中kiss1的表达水平(Ogawa et al, 2012)，而Kiss2促进了半滑舌鳎下丘脑中kiss2的表达水平(Wang et al, 2017a)。腹腔注射Kiss1促进了黑头呆鱼脑kiss2r的表达水平(Filby et al, 2008)。然而，埋植Kiss1和Kiss2均不影响黄条
促性腺激素抑制激素(Gonadotropin-inhibitory hormone, GnIH)是迄今为止在脊椎动物中鉴定出的唯一具有抑制生殖功能的下丘脑神经肽，通过其受体GnIHR (之前被称作GPR147)介导作用于脑-垂体-性腺轴进而影响动物生殖调控(Tsutsui et al, 2010; Ubuka et al, 2016; Wang et al, 2018)。目前，从鱼类到哺乳类都鉴定出了gnih/gnihr的同源基因，并且每种鱼类gnih基因编码有2种或者3种成熟多肽，即GnIH-1、GnIH-2及GnIH-3 (Ogawa et al, 2014; Tsutsui et al, 2010; Ubuka et al, 2016; 王滨等, 2016)。GnIH对kiss/kissr的表达调控也有少数报道。在半滑舌鳎中，GnIH-1和GnIH-2均不影响下丘脑中kiss2的表达水平(刘权等, 2017)。腹腔注射斜带石斑鱼3种GnIH多肽也不影响其下丘脑kiss2的表达水平(Wang et al, 2015)。此外，哺乳类GnIH同源多肽RFRP3也不影响大鼠kiss1表达水平(Johnson et al, 2008)。尽管侧脑室注射欧洲海鲈GnIH-1不影响其脑kiss1、kiss2、kiss1r及kiss2r的表达水平，但是，GnIH-2均降低了kiss1、kiss2及kiss1r的表达水平，这说明在欧洲海鲈中，GnIH-2主要发挥了生殖调控的抑制作用(Paullada-Salmeron et al, 2016)。
尽管Kiss能够通过直接作用于GnRH神经元，促进GnRH分泌进而上调生殖轴，GnRH也能够反作用于kiss/kissr系统，进而影响其表达调控。GnRH类似物(D-Ala6, Pro9Net)-mGnRHa促进了欧洲海鲈垂体细胞kiss2的表达水平，对kiss1r及kiss2r表达水平无影响(Espigares et al, 2015b)。同样，GnRH类似物不影响黄条
光照是影响鱼类及其他脊椎动物生殖调控的一个重要环境因子，其作用主要由松果体夜间分泌的褪黑激素介导(Kitahashi et al, 2013)。目前，关于光照对鱼类kiss/kissr系统的表达调控研究相对较少且存在争议。如持续性光照降低了罗非鱼脑kiss2r的表达水平，表明光照能够以直接或者间接的方式影响kiss2r的表达(Martinez-Chavez et al, 2008)。同样，持续性光照导致欧洲海鲈前中脑kiss1及kiss1r的表达量不再随季节变化而变化(Espigares et al, 2017)。长光照(繁殖状态)条件下，青鳉下丘脑核腹侧结节中Kiss1神经元的数量显著性高于短光照(非繁殖状态) (Kanda et al, 2008)。而在模拟自然光照(促进生殖)条件和持续性光照(抑制生殖)条件下，大西洋鳕(Gadus morhua)脑kiss2及kiss2r的表达量无显著性差异，这说明光照不影响大西洋鳕kiss2/kiss2r基因表达(Cowan et al, 2012)。特别是褪黑激素促进了斑马鱼脑kiss1及kiss2的表达水平(Carnevali et al, 2011)，却抑制了欧洲海鲈脑kiss1及kiss2的表达水平(Alvarado et al, 2015)。综上所示，Kiss/KissR系统可能介导了光照(及褪黑激素)对鱼类生殖调控过程，然而具体作用机制因物种而异，需要进一步深入研究。
6.4 温度对kiss/kissr系统的调控作用对变温动物而言，温度是影响其生殖调控的一个重要环境因子。水温升高或者降低均能抑制鱼类生殖，但其分子机制仍不清楚。Kiss作为鱼类生殖调控的一个重要因子，温度对kiss/kissr基因的表达调控作用也有了初步研究。斑马鱼最适繁殖温度为26℃~ 28℃，低于20℃或者高于30℃均能降低其繁殖能力(Shahjahan et al, 2013)。将斑马鱼置于低温(15℃)、正常温度(27℃)和高温(35℃) 7 d后研究发现，低温组斑马鱼全脑kiss1的表达量显著性增加，高温组kiss1的表达量与正常组相比无显著性差异；而低温组和高温组斑马鱼全脑kiss2的表达量较正常组均显著性降低(Shahjahan et al, 2013)。此外，低温也增加了斑马鱼松果体等部分脑区kiss1r的表达量，然而，低温和高温均降低了斑马鱼下丘脑等部分脑区kiss2r的表达量(Shahjahan et al, 2013)。上述结果表明，温度调控斑马鱼kiss1/kiss1r及kiss2/kiss2r表达的作用机制是不同的，低温激活了kiss1/kiss1r系统，而低温和高温均抑制了kiss2/kiss2r系统，说明kiss1/kiss1r和kiss2/ kiss2r系统可能参与了斑马鱼不同的生理功能(Shahjahan et al, 2013)。
同样，将星点东方鲀置于低温(14℃)、正常温度(21℃)和高温(28℃) 7 d后研究发现，低温组和高温组性腺指数GSI显著性降低；低温组和高温组脑kiss2/kiss2r表达量也显著性降低；与此同时，低温和高温组均抑制了脑gnrh1、垂体fshβ及lhβ的表达水平(Shahjahan et al, 2016)。上述结果表明，低温和高温组通过抑制kiss/gnrh1/gth系统，进而阻断星点东方鲀生殖。银汉鱼(Odontesthes bonariensis)的性别决定、分化与温度紧密相关，低温(17℃~19℃)导致100%全雌，高温(29℃)导致100%全雄，而24℃~25°℃导致雌雄比例各半(Tovar Bohorquez et al, 2017)。在高温条件下，银汉仔鱼整个脑部kiss2的表达量在孵化后4周显著性增加；而在低温条件下，脑部kiss2的表达量在孵化后8周内保持不变，这表明Kiss2可能在雄性发育过程中性别决定阶段发挥了重要作用(Tovar Bohorquez et al, 2017)。
6.5 饥饿对kiss/kissr系统的调控作用营养状况也会影响动物生殖活动。目前，关于Kiss介导的能量平衡与生殖之间关系的研究较少。在哺乳类中，饥饿导致小鼠(Mus musculus)下丘脑kiss1及kiss1r表达量降低(Luque et al, 2007)。同样，饥饿也降低了大鼠下丘脑kiss1的表达量，却增加了kiss1r的表达量(Castellano et al, 2005)。在鱼类中，饥饿15 d导致塞内加尔鳎体重减少，却增加了下丘脑kiss2及kiss2r的表达水平，但对胃中kiss2及kiss2r的表达水平无影响(Mechaly et al, 2011)。同样，饥饿也增加了欧洲海鲈下丘脑kiss1、kiss2、kiss1r及kiss2r的表达水平(Escobar et al, 2016)。综上所述，饥饿对哺乳类和鱼类kiss/kissr系统的不同调控作用表明，该系统可能在哺乳类和鱼类能量平衡过程中起着相反的作用。此外，Kiss/KissR系统是否参与了鱼类摄食调控仍不得而知，需要进一步深入研究。
7 小结Kiss是一种多功能的神经肽，它在下丘脑-垂体-性腺轴多个水平参与了哺乳动物生殖调控。目前，尽管已在多种鱼类中鉴定出了Kiss/KissR系统，但其在鱼类生殖调控中的精确作用需要进一步研究；Kiss调控垂体激素分泌及其基因表达的信号转导机制网络需要进一步完善；Kiss是否参与鱼类摄食调控及其作用机制尚未阐明；Kiss与其他因子(例如GnIH、GnRH等)之间如何互作，在生殖轴各个水平将多种信号整合进而调控生殖等生理过程仍不清楚，只有阐明上述机制才能更好地了解Kiss参与鱼类生殖、生长及代谢的协调过程。该综述总结了鱼类Kiss及其受体的研究进展，并对Kiss的生理学功能、信号转导机制以及kiss/kissr表达调控研究进行概括讨论，增加了人们对Kiss/KissR系统参与鱼类生殖调控机制的认识，为后续研究提供参考。
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