Supplemental information for Sander et al., Transcriptional profiling of the zebrafish proximal tubule

The hepatocyte nuclear factor 1 beta (Hnf1b) transcription factor is a key regulator of kidney tubule formation and is associated with a syndrome of renal cysts and early onset diabetes. To further our understanding of Hnf1b in the developing zebrafish kidney, we have performed RNA-Seq of proximal tubules from hnf1b-deficient larvae. This analysis revealed an enrichment of gene transcripts encoding transporters of the solute carrier (SLC) superfamily, including multiple members of the slc2 and slc5 glucose transporters. An investigation of the expression of slc2a1a, slc2a2, slc5a2, as well as a poorly studied glucose/mannose transporter encoded by slc5a9, revealed that these genes undergo dynamic spatiotemporal changes during tubule formation and maturation. A comparative analysis of zebrafish SLC genes with those expressed in mouse proximal tubules showed a substantial overlap at the level of gene families, indicating a high degree of functional conservation between zebrafish and mammalian proximal tubules. Taken together, our findings are consistent with a role for Hnf1b as a critical determinant of proximal tubule transport function by acting upstream of a large number of SLC genes and validate the zebrafish as a physiologically relevant model of the mammalian proximal tubule.<br><br>

肝细胞核因子1β（Hepatocyte nuclear factor 1 beta，Hnf1b）转录因子是肾小管形成的关键调控因子，与肾囊肿和早发性糖尿病综合征相关。为深入理解Hnf1b在斑马鱼肾脏发育中的作用，我们对hnf1b缺陷型幼鱼的近端小管进行了RNA测序（RNA-Seq）。该分析显示，编码溶质载体（solute carrier，SLC）超家族转运体的基因转录本显著富集，包括slc2和slc5葡萄糖转运体家族的多个成员。对slc2a1a、slc2a2、slc5a2以及slc5a9编码的一种研究较少的葡萄糖/甘露糖转运体的表达分析表明，这些基因在肾小管形成和成熟过程中经历动态的时空变化。将斑马鱼SLC基因与小鼠近端小管中表达的SLC基因进行比较分析，发现基因家族水平上存在显著重叠，表明斑马鱼与哺乳动物近端小管之间具有高度的功能保守性。综上，我们的研究结果表明，Hnf1b通过在大量SLC基因上游发挥作用，成为近端小管转运功能的关键决定因素；同时验证了斑马鱼作为哺乳动物近端小管生理相关模型的有效性。