Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2.

IF 4 3区 医学 Q2 CELL BIOLOGY Disease Models & Mechanisms Pub Date : 2024-10-17 DOI:10.1242/dmm.050862
Ayyappa Raja Desingu Rajan, Yuanyun Huang, Jan Stundl, Katelyn Chu, Anushka Irodi, Zihan Yang, Brian E Applegate, Marianne E Bronner
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Abstract

Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

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通过诱导性敲除 nf2 生成斑马鱼神经纤维瘤病模型。
神经纤维瘤病 2 型(NF-2)是一种显性遗传性疾病,由肿瘤抑制基因神经纤维瘤蛋白 2(NF2)基因突变引起。在此,我们报告了通过诱导性基因敲除 nf2a/b(人类 NF2 的斑马鱼同源基因)而产生的神经纤维瘤病条件性斑马鱼模型。对 nf2a 和 nf2b 表达的分析表明,nf2b 在早期胚胎中无处不在,在神经嵴及其衍生物和颅骨间质中有重叠表达。相比之下,nf2a的表达水平较低。在早期阶段诱导 nf2a/b 基因敲除会增加幼体许旺细胞和脑膜成纤维细胞的增殖。随后,在成年斑马鱼中,nf2a/b 基因敲除会引发一系列肿瘤的发生,包括前庭许旺瘤、脊髓许旺瘤、脑膜瘤和视网膜仓鼠瘤,这与在 NF-2 患者中观察到的肿瘤表现一致。总之,这些研究结果突显了一种新型斑马鱼模型的产生,它模拟了人类 NF-2 疾病的复杂性。因此,该模型在促进治疗筛选和阐明与 NF-2 发病有关的关键驱动基因方面具有巨大潜力。
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来源期刊
Disease Models & Mechanisms
Disease Models & Mechanisms 医学-病理学
CiteScore
6.60
自引率
7.00%
发文量
203
审稿时长
6-12 weeks
期刊介绍: Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.
期刊最新文献
The role of mesenchymal cells in cholangiocarcinoma. High-fat and high-sucrose diets induce an experimental rabbit model for age-related macular degeneration (AMD). Early life cisplatin exposure induces nerve growth factor mediated neuroinflammation and chemotherapy induced neuropathic pain. Hippo signaling cooperates with p53 to regulate lung airway mucous cell metaplasia. Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2.
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