脊椎动物钠-碘转运体(NIS或SLC5A5)将碘化物转运到合成甲状腺激素的甲状腺滤泡细胞中。SLC5A蛋白家族包括维生素的转运蛋白,矿物,和营养。高氯酸盐破坏SLC5A5功能,一种普遍的环境污染物,导致人类病理,尤其是甲状腺功能减退.高氯酸盐还会破坏模型动物的性发育,包括三松棘鱼(Gasterosteusaculeatus)和斑马鱼(Daniorerio),但其作用机制尚不清楚。为了检验SLC5A5旁系同源物在生殖器官发育所必需的组织中表达的假设,因此,似乎是介导高氯酸盐对性发育影响的候选人,我们首先调查了Slc5a旁系同源物的进化史,以更好地了解该基因家族的潜在功能轨迹.我们确定了相对于钠/胆碱协同转运蛋白(slc5a7)的两个slc5a旁系分子;这些进化枝是钠/碘化物和乳酸协同转运蛋白的NIS进化枝(slc5a5,slc5a6,slc5a8,slc5a8和slc5a12)和SGLTclade,5scl2,sla5和5crencorters。我们还表征了slc5a基因在发育过程中的表达模式。粘回胚胎和早期幼虫在结缔组织中表达NIS进化枝基因,软骨,牙齿,和甲状腺。Stickleback雄性和雌性在性腺中表达slc5a5及其旁系同源物。斑马鱼性别基因分型性腺上的单细胞转录组学(scRNA-seq)表明,表达NIS进化枝的细胞包括生殖细胞(slc5a5,slc5a6a,和slc5a6b)和性腺体细胞(slc5a8l)。这些结果与高氯酸盐通过与生殖组织中的slc5a5或其旁系同源物相互作用而对性发育产生影响的假设一致。这些发现显示slc5基因在stickleback和斑马鱼中的新表达结构域,这表明包括人类在内的脊椎动物的功能相似,并提供候选人来介导高氯酸盐对性发育的影响。
The vertebrate sodium-iodide symporter (NIS or
SLC5A5) transports iodide into the thyroid follicular cells that synthesize thyroid hormone. The SLC5A protein family includes transporters of vitamins, minerals, and nutrients. Disruption of
SLC5A5 function by perchlorate, a pervasive environmental contaminant, leads to human pathologies, especially hypothyroidism. Perchlorate also disrupts the sexual development of model animals, including threespine stickleback (Gasterosteus aculeatus) and zebrafish (Danio rerio), but the mechanism of action is unknown. To test the hypothesis that
SLC5A5 paralogs are expressed in tissues necessary for the development of reproductive organs, and therefore are plausible candidates to mediate the effects of perchlorate on sexual development, we first investigated the evolutionary history of Slc5a paralogs to better understand potential functional trajectories of the gene family. We identified two clades of slc5a paralogs with respect to an outgroup of sodium/choline cotransporters (slc5a7); these clades are the NIS clade of sodium/iodide and lactate cotransporters (
slc5a5, slc5a6, slc5a8, slc5a8, and slc5a12) and the SGLT clade of sodium/glucose cotransporters (slc5a1, slc5a2, slc5a3, slc5a4, slc5a10, and slc5a11). We also characterized expression patterns of slc5a genes during development. Stickleback embryos and early larvae expressed NIS clade genes in connective tissue, cartilage, teeth, and thyroid. Stickleback males and females expressed
slc5a5 and its paralogs in gonads. Single-cell transcriptomics (scRNA-seq) on zebrafish sex-genotyped gonads revealed that NIS clade-expressing cells included germ cells (slc5a5, slc5a6a, and slc5a6b) and gonadal soma cells (slc5a8l). These results are consistent with the hypothesis that perchlorate exerts its effects on sexual development by interacting with slc5a5 or its paralogs in reproductive tissues. These findings show novel expression domains of slc5 genes in stickleback and zebrafish, which suggest similar functions across vertebrates including humans, and provide candidates to mediate the effects of perchlorate on sexual development.