Division of Cardiology, Pediatric Institute for Heart Regeneration and Therapeutics (I-HRT), UPMC Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, USA; Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Departments of Medicine and Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Dev Cell. 2022 Oct 24;57(20):2397-2411.e9. doi: 10.1016/j.devcel.2022.09.017.
Nuclear pores are essential for nuclear-cytoplasmic transport. Whether and how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we show that rat heart muscle cells (cardiomyocytes) undergo a 63% decrease in nuclear pore numbers during maturation, and this changes their responses to extracellular signals. The maturation-associated decline in nuclear pore numbers is associated with lower nuclear import of signaling proteins such as mitogen-activated protein kinase (MAPK). Experimental reduction of nuclear pore numbers decreased nuclear import of signaling proteins, resulting in decreased expression of immediate-early genes. In a mouse model of high blood pressure, reduction of nuclear pore numbers improved adverse heart remodeling and reduced progression to lethal heart failure. The decrease in nuclear pore numbers in cardiomyocyte maturation and resulting functional changes demonstrate how terminally differentiated cells permanently alter their handling of information flux across the nuclear envelope and, with that, their behavior.
核孔对于核质运输至关重要。细胞是否以及如何改变核孔以改变核运输和细胞功能尚不清楚。在这里，我们发现大鼠心肌细胞（心肌细胞）在成熟过程中核孔数量减少了 63%，这改变了它们对外界信号的反应。与核孔数量减少相关的成熟相关下降与信号蛋白（如丝裂原活化蛋白激酶（MAPK））的核内输入减少有关。核孔数量的实验减少降低了信号蛋白的核内输入，导致即时早期基因的表达减少。在高血压的小鼠模型中，核孔数量的减少改善了心脏的不良重构，并减少了向致命性心力衰竭的进展。心肌细胞成熟过程中核孔数量的减少以及由此产生的功能变化表明，终末分化细胞如何永久性地改变其对核膜跨越的信息流的处理方式，以及随之改变其行为。
