ErbB4可变剪接在体外介导胎鼠II型肺泡细胞分化。
ErbB4 alternative splicing mediates fetal mouse alveolar type II cell differentiation in vitro.
作者信息
Wiegel Dorothea, Dammann Christiane E L, Nielsen Heber C
机构信息
Hannover Medical School, 30625, Hannover, Germany.
Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, Boston, MA, 02111, USA.
出版信息
Pediatr Res. 2022 Mar 25. doi: 10.1038/s41390-022-02013-y.
BACKGROUND
Alternative splicing (AS) creates different protein isoforms, an important mechanism regulating cell-specific function. Little is known about AS in lung development, particularly in alveolar type II (ATII) cells. ErbB4 receptor isoforms Jma and Jmb have significant and opposing functions in the brain, heart, and lung development and/or disease. However, the regulators of ErbB4 AS are unknown. ErbB4 AS regulators in fetal mouse ATII cells control its function in ATII cell maturation.
METHODS
Candidate ErbB4 AS regulators were found using in silico analysis. Their developmental expression was studied in fetal mouse ATII cells. The effects of splice factor downregulation and upregulation on ATII cell maturation were analyzed.
RESULTS
ErbB4-Jma increased significantly in ATII cells after gestation E16.5. In silico analysis found four candidate splice factors: FOX2, CUG/CELF1, TIAR, and HUB. Fetal ATII cells expressed these factors in distinct developmental profiles. HUB downregulation in E17.5 ATII cells increased Jma isoform levels and Sftpb gene expression and decreased Jmb. HUB overexpression decreased Jma and Sftpb.
CONCLUSIONS
ErbB4 AS is developmentally controlled by HUB in fetal ATII cells, promoting ATII differentiation. Regulated AS expression during ATII cell differentiation suggests novel therapeutic strategies to approach human disease.
IMPACT
Alternative splicing (AS) of the ErbB4 receptor, involving mutually exclusive exon inclusion, creates Jma and Jmb isoforms with distinct differences in receptor processing and function. The Jma isoform of ErbB4 promotes differentiation of fetal lung alveolar type II cells. The AS is mediated in part by the RNA-binding protein HUB. The molecular mechanism of AS for ErbB4 has not been previously described. The regulation of ErbB4 AS has important implications in the development of organs, such as the lung, brain, and heart, and for disease, including cancer.
背景
可变剪接（AS）可产生不同的蛋白质异构体，是调节细胞特异性功能的重要机制。目前对肺发育过程中的可变剪接了解甚少，尤其是在II型肺泡（ATII）细胞中。ErbB4受体异构体Jma和Jmb在脑、心脏和肺的发育及/或疾病中具有显著且相反的功能。然而，ErbB4可变剪接的调节因子尚不清楚。胎儿小鼠ATII细胞中的ErbB4可变剪接调节因子控制其在ATII细胞成熟中的功能。
方法
通过计算机分析找到候选的ErbB4可变剪接调节因子。研究它们在胎儿小鼠ATII细胞中的发育表达情况。分析剪接因子下调和上调对ATII细胞成熟的影响。
结果
妊娠E16.5后，ATII细胞中的ErbB4-Jma显著增加。计算机分析发现了四个候选剪接因子：FOX2、CUG/CELF1、TIAR和HUB。胎儿ATII细胞以不同的发育模式表达这些因子。在E17.5的ATII细胞中下调HUB可增加Jma异构体水平和Sftpb基因表达，并降低Jmb。过表达HUB则降低Jma和Sftpb。
结论
在胎儿ATII细胞中，ErbB4可变剪接受HUB的发育调控，促进ATII分化。ATII细胞分化过程中可变剪接表达的调控提示了针对人类疾病的新治疗策略。
影响
ErbB4受体的可变剪接涉及互斥外显子的包含，产生了在受体加工和功能上有明显差异的Jma和Jmb异构体。ErbB4的Jma异构体促进胎儿肺II型肺泡细胞的分化。这种可变剪接部分由RNA结合蛋白HUB介导。此前尚未描述ErbB4可变剪接的分子机制。ErbB4可变剪接的调控对肺、脑和心脏等器官的发育以及包括癌症在内的疾病具有重要意义。
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