The link of FOXO1 and FOXO4 transcription factors to development of the lens.

IF 2 3区 生物学 Q2 ANATOMY & MORPHOLOGY Developmental Dynamics Pub Date : 2025-01-11 DOI:10.1002/dvdy.766
Rifah N Gheyas, Ruby C Williams, Kelly A Ryan, A Sue Menko
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Abstract

Background: The FOXOs regulate the transcription of many genes, including ones directly linked to pathways required for lens development. However, this transcription factor family has rarely been studied in the context of development, including the development of the lens. FOXO expression, regulation, and function during lens development remained unexplored.

Results: In studies of the embryonic lens, we showed that both FOXO1 and FOXO4, which share many downstream targets, are expressed in a differentiation-state-specific manner, most highly in lens epithelial and differentiating cortical fiber cells. Their expression patterns and subcellular distributions suggest both shared and distinct functions. Stabilization of FOXO cytoplasmic pools involved their binding to the chaperone protein 14-3-3. FOXO association with β-catenin linked this transcription complex to fiber cell-specific gene activation. Inhibition of PI3K/Akt signaling promoted FOXO1/FOXO4 nuclear localization in lens epithelial and fiber cells and expression of the CDKi p27 in the lens epithelium where it has been linked to lens cell withdrawal from the cell cycle and initiation of the lens differentiation program. We showed that FOXO1 transcriptional activation is required for the induction of p27 when Akt signaling is blocked, demonstrating the linearity of the PI3K/Akt/FOXO1/p27 pathway.

Conclusions: PI3K/Akt signaling regulates FOXO-dependent lens cell differentiation.

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FOXO1和FOXO4转录因子与晶状体发育的联系。
背景:FOXOs调节许多基因的转录,包括与晶状体发育所需途径直接相关的基因。然而,这个转录因子家族很少在发育的背景下进行研究,包括晶状体的发育。FOXO在晶状体发育过程中的表达、调控和功能仍未被研究。结果:在胚胎晶状体的研究中,我们发现FOXO1和FOXO4都以分化状态特异性的方式表达,在晶状体上皮细胞和分化的皮质纤维细胞中表达最多。它们的表达模式和亚细胞分布表明它们既有共同的功能,也有不同的功能。FOXO细胞质池的稳定与它们与伴侣蛋白14-3-3的结合有关。FOXO与β-连环蛋白的结合将这种转录复合物与纤维细胞特异性基因激活联系起来。PI3K/Akt信号的抑制促进了FOXO1/FOXO4在晶状体上皮细胞和纤维细胞中的核定位,以及CDKi p27在晶状体上皮中的表达,这与晶状体细胞退出细胞周期和晶状体分化程序的启动有关。我们发现,当Akt信号被阻断时,诱导p27需要FOXO1的转录激活,这证明了PI3K/Akt/FOXO1/p27通路的线性。结论:PI3K/Akt信号调控foxo依赖性晶状体细胞分化。
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来源期刊
Developmental Dynamics
Developmental Dynamics 生物-发育生物学
CiteScore
5.10
自引率
8.00%
发文量
116
审稿时长
3-8 weeks
期刊介绍: Developmental Dynamics, is an official publication of the American Association for Anatomy. This peer reviewed journal provides an international forum for publishing novel discoveries, using any model system, that advances our understanding of development, morphology, form and function, evolution, disease, stem cells, repair and regeneration.
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An analysis of contractile and protrusive cell behaviors at the superficial surface of the zebrafish neural plate. Active cell proliferation contributes to the enlargement of the nascent nucleus pulposus. Loss of the epithelial transcription factor grhl3 leads to variably penetrant developmental phenotypes in zebrafish. β-Catenin localization in the ctenophore Mnemiopsis leidyi suggests an ancestral role in cell adhesion and nuclear function. Cover Image
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