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首页> 外文期刊>Development >Loss of MAP3K1 enhances proliferation and apoptosis during retinal development.
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Loss of MAP3K1 enhances proliferation and apoptosis during retinal development.

机译:MAP3K1的丢失会增强视网膜发育过程中的增殖和凋亡。

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摘要

Precise coordination of progenitor cell proliferation and differentiation is essential for proper organ morphogenesis and function during mammalian development. The mitogen-activated protein kinase kinase kinase 1 (MAP3K1) has a well-established role in anterior eyelid development, as Map3k1-knockout mice have defective embryonic eyelid closure and an `eye-open at birth' (EOB) phenotype. Here, we show that MAP3K1 is highly expressed in the posterior of the developing eye and is required for retina development. The MAP3K1-deficient mice exhibit increased proliferation and apoptosis, and Muller glial cell overproduction in the developing retinas. Consequently, the retinas of these mice show localized rosette-like arrangements in the outer nuclear layer, and develop abnormal vascularization, broken down retinal pigment epithelium, photoreceptor loss and early onset of retinal degeneration. Although the retinal defect is associated with increased cyclin D1 and CDK4/6 expression, and RB phosphorylation and E2F-target gene upregulation, it is independent of the EOB phenotype and of JNK. The retinal developmental defect still occurs in knockout mice that have undergone tarsorrhaphy, but is absent in compound mutant Map3k1(+/DeltaKD)Jnk1(-/-) and Map3k1(+/DeltaKD)Jnk(+/-)Jnk2(+/-) mice that have EOB and reduced JNK signaling. Our results unveil a novel role for MAP3K1 in which it crosstalks with the cell cycle regulatory pathways in the prevention of retina malformation and degeneration.
机译:祖细胞增殖和分化的精确协调对于哺乳动物发育过程中适当的器官形态发生和功能至关重要。有丝分裂原激活的蛋白激酶激酶激酶1(MAP3K1)在前眼睑发育中具有公认的作用,因为Map3k1基因敲除小鼠的胚胎眼睑闭合性很差,并且具有“出生时睁眼”(EOB)的表型。在这里,我们显示MAP3K1在发育中的眼后部高度表达,是视网膜发育所必需的。 MAP3K1缺陷小鼠表现出增加的增殖和凋亡,以及在发育中的视网膜中的穆勒神经胶质细胞过度生产。因此,这些小鼠的视网膜在外核层中显示出局部的玫瑰花状排列,并出现异常的血管形成,视网膜色素上皮分解,感光细胞丢失和视网膜变性的早期发作。尽管视网膜缺损与细胞周期蛋白D1和CDK4 / 6表达增加,RB磷酸化和E2F靶基因上调有关,但它与EOB表型和JNK无关。视网膜发育缺陷仍然发生在睑板漏的敲除小鼠中,但在复合突变体Map3k1(+ / DeltaKD)Jnk1(-/-)和Map3k1(+ / DeltaKD)Jnk(+/-)Jnk2(+/-)中却不存在)具有EOB并减少JNK信号传导的小鼠。我们的研究结果揭示了MAP3K1在预防视网膜畸形和变性中与细胞周期调控途径发生相互作用的新作用。

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