Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney

New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population.

哺乳动物的肾发生（nephrogenesis）在出生前后停止，成体中完全缺失。与之相对，鱼类与两栖类的中肾（mesonephros）在胚胎发育后仍存在明确的肾发生过程。爬行类（含鸟类）与哺乳类的暂时性中肾会在胚胎发育阶段被后肾（metanephros）取代。据此可推测，胚胎发育后的肾发生仅局限于中肾。既往研究提示，非鸟类爬行类（下文简称爬行类）的后肾可在终生持续形成肾单位。本研究通过检测红耳滑龟（Trachemys scripta）、锦龟（Chrysemys picta）、红尾蚺（Boa constrictor）、阿根廷黑白泰加蜥（Tupinambis tegu）、安乐蜥（Anolis carolinensis）以及密西西比短吻鳄（Alligator mississipiensis）等多个物种的成体肾脏，探究了爬行类成体肾发生的存在性。研究发现，所有主要爬行类类群（龟鳖目Testudines、鳄目Crocodylia与有鳞目Squamates）均存在成体肾发生现象。不同物种间肾发生的总量差异显著，其中龟类的肾发生密度最高。与之相反，我们未能在单孔目（monotremes）动物以及鬣蜥科安乐蜥（A. carolinensis）中检测到成体肾发生。肾单位祖细胞表达转录因子Six2，在哺乳动物中，随着祖细胞群体耗尽、肾发生终止，Six2的表达会被下调。以密西西比短吻鳄为模型，我们在成体肾脏中检测到了Six2阳性的帽状间充质（cap mesenchyme）细胞，其空间分布与肾发生区域高度吻合。上述结果表明，爬行类的后肾保留了胚胎发育后持续生成新肾单位的能力，这一过程在哺乳类演化早期便已丢失，其潜在原因可能是Six2阳性祖细胞群体的持续存在。