Kim Ki-Hyun, Antkiewicz Dagmara S, Yan Long, Eliceiri Kevin W, Heideman Warren, Peterson Richard E, Lee Youngsook
Department of Anatomy, School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
Dev Biol. 2007 Aug 15;308(2):494-506. doi: 10.1016/j.ydbio.2007.06.005. Epub 2007 Jun 13.
Leucine-rich Repeat Containing protein 10 (LRRC10) has recently been identified as a cardiac-specific factor in mice. However, the function of this factor remains to be elucidated. In this study, we investigated the developmental roles of Lrrc10 using zebrafish as an animal model. Knockdown of Lrrc10 in zebrafish embryos (morphants) using morpholinos caused severe cardiac morphogenic defects including a cardiac looping failure accompanied by a large pericardial edema, and embryonic lethality between day 6 and 7 post fertilization. The Lrrc10 morphants exhibited cardiac functional defects as evidenced by a decrease in ejection fraction and cardiac output. Further investigations into the underlying mechanisms of the cardiac defects revealed that the number of cardiomyocyte was reduced in the morphants. Expression of two cardiac genes was deregulated in the morphants including an increase in atrial natriuretic factor, a hallmark for cardiac hypertrophy and failure, and a decrease in cardiac myosin light chain 2, an essential protein for cardiac contractility in zebrafish. Moreover, a reduced fluorescence intensity from NADH in the morphant heart was observed in live zebrafish embryos as compared to control. Taken together, the present study demonstrates that Lrrc10 is necessary for normal cardiac development and cardiac function in zebrafish embryos, which will enhance our understanding of congenital heart defects and heart disease.
富含亮氨酸重复序列蛋白10（LRRC10）最近被鉴定为小鼠心脏特异性因子。然而，该因子的功能仍有待阐明。在本研究中，我们以斑马鱼为动物模型，研究了Lrrc10在发育过程中的作用。使用吗啉代寡核苷酸敲低斑马鱼胚胎（形态突变体）中的Lrrc10，导致严重的心脏形态发生缺陷，包括心脏环化失败并伴有大量心包水肿，以及受精后第6至7天胚胎死亡。Lrrc10形态突变体表现出心脏功能缺陷，射血分数和心输出量降低证明了这一点。对心脏缺陷潜在机制的进一步研究表明，形态突变体中心肌细胞数量减少。形态突变体中两个心脏基因的表达失调，包括心房利钠因子增加，这是心脏肥大和衰竭的标志，以及心肌肌球蛋白轻链2减少，这是斑马鱼心脏收缩所必需的蛋白质。此外，与对照组相比，在活斑马鱼胚胎中观察到形态突变体心脏中NADH荧光强度降低。综上所述，本研究表明Lrrc10是斑马鱼胚胎正常心脏发育和心脏功能所必需的，这将增进我们对先天性心脏病和心脏病的理解。
