Petersen Ann M, Small Clayton M, Yan Yi-Lin, Wilson Catherine, Batzel Peter, Bremiller Ruth A, Buck C Loren, von Hippel Frank A, Cresko William A, Postlethwait John H
Department of Biology, Institute of Ecology and Evolution University of Oregon Eugene Oregon USA.
J.J. Howard Marine Lab, Northeast Fisheries Science Center National Oceanographic and Atmospheric Administration Sandy Hook New Jersey USA.
Evol Appl. 2022 Jul 7;15(7):1079-1098. doi: 10.1111/eva.13424. eCollection 2022 Jul.
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 () and zebrafish (), 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 paralogs to better understand potential functional trajectories of the gene family. We identified two clades of paralogs with respect to an outgroup of sodium/choline cotransporters (); these clades are the NIS clade of sodium/iodide and lactate cotransporters (, , , , and ) and the SGLT clade of sodium/glucose cotransporters (, , , , , and ). We also characterized expression patterns of genes during development. Stickleback embryos and early larvae expressed NIS clade genes in connective tissue, cartilage, teeth, and thyroid. Stickleback males and females expressed and its paralogs in gonads. Single-cell transcriptomics (scRNA-seq) on zebrafish sex-genotyped gonads revealed that NIS clade-expressing cells included germ cells (, , and ) and gonadal soma cells (). These results are consistent with the hypothesis that perchlorate exerts its effects on sexual development by interacting with or its paralogs in reproductive tissues. These findings show novel expression domains of 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.
脊椎动物钠碘同向转运体（NIS或SLC5A5）将碘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、矿物质和营养物质的转运体。高氯酸盐是一种普遍存在的环境污染物，它对SLC5A5功能的破坏会导致人类疾病，尤其是甲状腺功能减退。高氯酸盐还会干扰模式动物（包括三刺鱼和斑马鱼）的性发育，但其作用机制尚不清楚。为了验证SLC5A5旁系同源物在生殖器官发育所需组织中表达的假设，因此它们可能是介导高氯酸盐对性发育影响的候选者，我们首先研究了旁系同源物的进化历史，以更好地了解该基因家族的潜在功能轨迹。相对于钠/胆碱共转运体的一个外类群，我们鉴定出了两个旁系同源物分支；这些分支是钠/碘和乳酸共转运体的NIS分支（、、、、和）以及钠/葡萄糖共转运体的SGLT分支（、、、、、和）。我们还对发育过程中基因的表达模式进行了表征。三刺鱼胚胎和早期幼体在结缔组织、软骨、牙齿和甲状腺中表达NIS分支基因。三刺鱼的雄性和雌性在性腺中表达及其旁系同源物。对斑马鱼性别基因分型的性腺进行单细胞转录组学（scRNA-seq）分析发现，表达NIS分支的细胞包括生殖细胞（、、和）和性腺体细胞（）。这些结果与高氯酸盐通过与生殖组织中的或其旁系同源物相互作用来影响性发育的假设一致。这些发现揭示了三刺鱼和斑马鱼中基因的新表达域，这表明包括人类在内的所有脊椎动物都具有相似的功能，并为介导高氯酸盐对性发育的影响提供了候选者。
