Department of Marine Biotechnology, Institute of Marine and Environmental Technology, University of Maryland Baltimore County, Baltimore, Maryland, USA.
Biol Reprod. 2018 Sep 1;99(3):565-577. doi: 10.1093/biolre/ioy078.
Gonadotropin-releasing hormone (GNRH) is known as a pivotal upstream regulator of reproduction in vertebrates. However, reproduction is not compromised in the hypophysiotropic Gnrh3 knockout line in zebrafish (gnrh3-/-). In order to determine if Gnrh2, the only other Gnrh isoform in zebrafish brains, is compensating for the loss of Gnrh3, we generated a double Gnrh knockout zebrafish line. Surprisingly, the loss of both Gnrh isoforms resulted in no major impact on reproduction, indicating that a compensatory response, outside of the Gnrh system, was evoked. A plethora of factors acting along the reproductive hypothalamus-pituitary axis were evaluated as possible compensators based on neuroanatomical and differential gene expression studies. In addition, we also examined the involvement of feeding factors in the brain as potential compensators for Gnrh2, which has known anorexigenic effects. We found that the double knockout fish exhibited upregulation of several genes in the brain, specifically gonadotropin-inhibitory hormone (gnih), secretogranin 2 (scg2), tachykinin 3a (tac3a), and pituitary adenylate cyclase-activating peptide 1 (pacap1), and downregulation of agouti-related peptide 1 (agrp1), indicating the compensation occurs outside of Gnrh cells and therefore is a noncell autonomous response to the loss of Gnrh. While the differential expression of gnih and agrp1 in the double knockout line was confined to the periventricular nucleus and hypothalamus, respectively, the upregulation of scg2 corresponded with a broader neuronal redistribution in the lateral hypothalamus and hindbrain. In conclusion, our results demonstrate the existence of a redundant reproductive regulatory system that comes into play when Gnrh2 and Gnrh3 are lost.
促性腺激素释放激素（GnRH）被认为是脊椎动物生殖的关键上游调节剂。然而，在斑马鱼（gnrh3-/-）的促垂体 GnRH3 敲除系中，生殖并未受到影响。为了确定 GnRH2 是否是斑马鱼脑中唯一的另一种 GnRH 同工型，正在补偿 GnRH3 的缺失，我们生成了一种双 GnRH 敲除斑马鱼系。令人惊讶的是，两种 GnRH 同工型的缺失都没有对生殖产生重大影响，这表明除了 GnRH 系统之外，还引发了一种补偿反应。根据神经解剖学和差异基因表达研究，评估了沿生殖下丘脑-垂体轴作用的大量因素，作为可能的补偿物。此外，我们还研究了脑内摄食因子作为 GnRH2 的潜在补偿物的参与情况，因为 GnRH2 具有已知的厌食作用。我们发现，双敲除鱼在脑中表现出许多基因的上调，特别是促性腺激素抑制激素（gnih）、分泌颗粒蛋白 2（scg2）、速激肽 3a（tac3a）和垂体腺苷酸环化酶激活肽 1（pacap1），而下调了 agouti 相关肽 1（agrp1），这表明补偿发生在 GnRH 细胞之外，因此是对 GnRH 缺失的非细胞自主反应。虽然双敲除系中 gnih 和 agrp1 的差异表达分别局限于室周核和下丘脑，但 scg2 的上调与外侧下丘脑和后脑中更广泛的神经元重新分布相对应。总之，我们的结果表明存在冗余的生殖调节系统，当 GnRH2 和 GnRH3 缺失时，该系统会发挥作用。
