Nucleolin loss of function leads to aberrant Fibroblast Growth Factor signaling and craniofacial anomalies.
Nucleolin loss of function leads to aberrant Fibroblast Growth Factor signaling and craniofacial anomalies.
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DOI：
10.1242/dev.200349
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发表时间：
2022-06-15
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影响因子：
--
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核糖体RNA（rRNA）转录和核糖体生物合成是所有细胞生长和增殖所需的全局过程，然而在脊椎动物中这些过程的扰动导致称为核糖体病的组织特异性缺陷。rRNA转录和加工蛋白的突变经常导致颅面异常;然而，这些缺陷的细胞和分子原因知之甚少。因此，我们研究了最丰富的核仁磷蛋白，核仁素（Ncl），在脊椎动物的发育功能。ncl突变（ncl−/−）斑马鱼表现出颅面异常，如下颌面发育不全。我们观察到ncl−/−突变体表现出rRNA合成减少和p53依赖性凋亡，与核糖体生物合成中的作用一致。然而，我们发现核仁素也执行与核糖体生物合成无关的功能。我们发现fgf 8a mRNA的半衰期在ncl−/−突变体中减少，这扰乱了Fgf信号传导，导致Sox 9a介导的软骨形成和Runx 2介导的骨形成失调。与该模型一致，外源性FGF 8处理显著挽救了ncl−/−斑马鱼的颅骨骼表型，表明核仁素调节骨软骨祖细胞分化。因此，我们的工作揭示了核仁素在胚胎颅面发育过程中rRNA转录和转录后生长因子信号调节中的组织特异性功能。总结：核糖体RNA加工蛋白核仁素功能的丧失导致斑马鱼颅面区域的软骨和骨发育不全，这可以通过补充FGF 8来挽救。
Ribosomal RNA (rRNA) transcription and ribosome biogenesis are global processes required for growth and proliferation of all cells, yet perturbation of these processes in vertebrates leads to tissue-specific defects termed ribosomopathies. Mutations in rRNA transcription and processing proteins often lead to craniofacial anomalies; however, the cellular and molecular reasons for these defects are poorly understood. Therefore, we examined the function of the most abundant nucleolar phosphoprotein, Nucleolin (Ncl), in vertebrate development. ncl mutant (ncl−/−) zebrafish present with craniofacial anomalies such as mandibulofacial hypoplasia. We observed that ncl−/− mutants exhibited decreased rRNA synthesis and p53-dependent apoptosis, consistent with a role in ribosome biogenesis. However, we found that Nucleolin also performs functions not associated with ribosome biogenesis. We discovered that the half-life of fgf8a mRNA was reduced in ncl−/− mutants, which perturbed Fgf signaling, resulting in misregulated Sox9a-mediated chondrogenesis and Runx2-mediated osteogenesis. Consistent with this model, exogenous FGF8 treatment significantly rescued the cranioskeletal phenotype in ncl−/− zebrafish, suggesting that Nucleolin regulates osteochondroprogenitor differentiation. Our work has therefore uncovered tissue-specific functions for Nucleolin in rRNA transcription and post-transcriptional regulation of growth factor signaling during embryonic craniofacial development. Summary: Loss of function of the ribosomal RNA processing protein Nucleolin results in cartilage and bone hypoplasia in the craniofacial region of zebrafish, which can be rescued by FGF8 supplementation.
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影响因子：
3.7
作者：
Cruz-Martinez P;Martinez-Ferre A;Jaramillo-Merchán J;Estirado A;Martinez S;Jones J
通讯作者：
Jones J
影响因子：
4.8
作者：
Friedrich, JK;Panov, KI;Zomerdijk, JCBM
通讯作者：
Zomerdijk, JCBM
影响因子：
4.5
作者：
Delhermite J;Tafforeau L;Sharma S;Marchand V;Wacheul L;Lattuca R;Desiderio S;Motorin Y;Bellefroid E;Lafontaine DLJ
通讯作者：
Lafontaine DLJ
DOI：
10.1073/pnas.0603730103
发表时间：
2006-09-05
影响因子：
11.1
作者：
Dixon, Jill;Jones, Natalie C.;Trainor, Paul A.
通讯作者：
Trainor, Paul A.
影响因子：
14.9
作者：
Abdelmohsen K;Tominaga K;Lee EK;Srikantan S;Kang MJ;Kim MM;Selimyan R;Martindale JL;Yang X;Carrier F;Zhan M;Becker KG;Gorospe M
通讯作者：
Gorospe M