Cancer Immunogenetics, University of Manchester, St Mary's Hospital, Manchester, United Kingdom.
PLoS One. 2010 Sep 10;5(9):e12667. doi: 10.1371/journal.pone.0012667.
Mammals are able to rapidly produce red blood cells in response to stress. The molecular pathways used in this process are important in understanding responses to anaemia in multiple biological settings. Here we characterise the novel gene Claudin 13 (Cldn13), a member of the Claudin family of tight junction proteins using RNA expression, microarray and phylogenetic analysis. We present evidence that Cldn13 appears to be co-ordinately regulated as part of a stress induced erythropoiesis pathway and is a mouse-specific gene mainly expressed in tissues associated with haematopoietic function. CLDN13 phylogenetically groups with its genomic neighbour CLDN4, a conserved tight junction protein with a putative role in epithelial to mesenchymal transition, suggesting a recent duplication event. Mechanisms of mammalian stress erythropoiesis are of importance in anaemic responses and expression microarray analyses demonstrate that Cldn13 is the most abundant Claudin in spleen from mice infected with Trypanosoma congolense. In mice prone to anaemia (C57BL/6), its expression is reduced compared to strains which display a less severe anaemic response (A/J and BALB/c) and is differentially regulated in spleen during disease progression. Genes clustering with Cldn13 on microarrays are key regulators of erythropoiesis (Tal1, Trim10, E2f2), erythrocyte membrane proteins (Rhd and Gypa), associated with red cell volume (Tmcc2) and indirectly associated with erythropoietic pathways (Cdca8, Cdkn2d, Cenpk). Relationships between genes appearing co-ordinately regulated with Cldn13 post-infection suggest new insights into the molecular regulation and pathways involved in stress induced erythropoiesis and suggest a novel, previously unreported role for claudins in correct cell polarisation and protein partitioning prior to erythroblast enucleation.
哺乳动物能够迅速产生红细胞以应对压力。在这个过程中使用的分子途径对于理解多种生物学环境中的贫血反应很重要。在这里，我们使用 RNA 表达、微阵列和系统发育分析来描述紧密连接蛋白 Claudin 家族的新基因 Claudin 13（Cldn13）。我们提出的证据表明，Cldn13 似乎作为应激诱导的红细胞生成途径的一部分协同调节，是一种主要在与造血功能相关的组织中表达的小鼠特异性基因。CLDN13 在系统发育上与它的基因组邻居 CLDN4 聚在一起，CLDN4 是一种保守的紧密连接蛋白，具有上皮细胞到间充质转化的潜在作用，表明最近发生了复制事件。哺乳动物应激性红细胞生成的机制在贫血反应中很重要，表达微阵列分析表明，Cldn13 是感染锥虫刚果（Trypanosoma congolense）的小鼠脾脏中最丰富的 Claudin。在容易发生贫血的小鼠（C57BL/6）中，与表现出较轻贫血反应的品系（A/J 和 BALB/c）相比，其表达减少，并且在疾病进展过程中脾脏中的表达不同。在微阵列上与 Cldn13 聚类的基因是红细胞生成的关键调节剂（Tal1、Trim10、E2f2）、红细胞膜蛋白（Rhd 和 Gypa）、与红细胞体积相关（Tmcc2）和间接与红细胞生成途径相关（Cdca8、Cdkn2d、Cenpk）。感染后与 Cldn13 协同调节的基因之间的关系表明，在应激诱导的红细胞生成中，分子调节和途径有了新的认识，并暗示 Claudin 在红细胞去核前正确的细胞极化和蛋白质分配中具有新的、以前未报道的作用。
