原发性纤毛运动障碍从胚胎发生到成年：Odad3功能缺失小鼠模型上气道阶段依赖性异常的Micro-CT分析

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中文摘要

背景/目的： 原发性纤毛运动障碍（PCD）是一种遗传异质性疾病，以纤毛功能受损为特征，导致慢性气道疾病。ODAD3（CCDC151）的功能缺失突变是患者中已确定的病因，Odad3缺陷小鼠可重现该病的关键特征。然而，Odad3缺失对上气道发育和功能的影响尚未被探索。本研究探讨了Odad3破坏在发育期间和成年动物中对上气道结构的后果。
方法： 对组成型（Odad3-/-）和诱导型条件性（Odad3icKO）小鼠模型，与杂合子和野生型同窝仔畜一起，在胚胎、出生后和成年阶段进行分析。采用优化的高分辨率三维微型计算机断层扫描（micro-CT或µCT）结合组织学，进行系统的基因型-表型评估，绘制上气道解剖结构图谱，并评估PCD疾病发病。
结果： 遗传学剖析揭示，表型显著依赖于Odad3缺失发生在发育期间还是成年期。组成型Odad3缺失导致胚胎阶段和出生后早期发育中出现广泛性颅面重塑和鼻甲发育不全。相反，成年期诱导的条件性缺失产生鼻甲局部尾侧萎缩，并伴有大量黏液积聚，与黏液纤毛清除受损一致，并提供了PCD小鼠模型中慢性鼻窦炎样病理的三维结构和形态学特征。杂合子Odad3icKO/+和Odad3+/-小鼠在表型上与野生型对照无法区分，表明单等位基因缺失不会破坏上气道形态。
结论： 本研究描述了PCD上气道病理的结构时间线，并验证了Odad3icKO模型作为研究纤毛病气道疾病的稳健三维结构表型分析平台。将靶向遗传破坏与三维µCT虚拟组织学相结合，为在PCD小鼠模型中全面研究人类遗传变异和基因敲除提供了一个强大的框架。

英文摘要

BACKGROUND/OBJECTIVES: Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired ciliary function, leading to chronic airway disease. Loss-of-function mutations in ODAD3 (CCDC151) represent an established cause in patients, and Odad3-deficient mice recapitulate key disease traits. However, the impact of Odad3 ablation on upper airway development and function remains unexplored. This study investigated the consequences of Odad3 disruption on upper airway structures during development and in adult animals.
METHODS: Constitutive (Odad3-/-) and inducible conditional (Odad3icKO) mouse models were analyzed alongside heterozygous and wild-type littermates during embryonic, postnatal, and adult stages. Optimized high-resolution 3D micro-computed tomography (micro-CT or µCT) combined with histology was utilized to conduct systematic genotype-phenotype evaluations, map upper airway anatomical architecture, and assess PCD disease onset.
RESULTS: Genetic dissection revealed a marked dependence of the phenotype on whether Odad3 loss occurred during development or in adulthood. Constitutive Odad3 deletion resulted in pervasive craniofacial remodeling and turbinate hypoplasia during embryonic stages and early postnatal development. Conversely, adult-induced conditional ablation produced localized caudal atrophy of the nasal turbinates accompanied by massive mucus accumulation, consistent with impaired mucociliary clearance and providing a 3D structural and morphological characterization of chronic rhinosinusitis-like pathology in PCD mouse models. Heterozygous Odad3icKO/+ and Odad3+/- mice were phenotypically indistinguishable from wild-type controls, indicating that single-allele loss does not disrupt upper airway morphology.
CONCLUSIONS: This study characterizes the structural timeline of upper airway pathology in PCD and validates the Odad3icKO model as a robust 3D structural phenotyping platform for investigating airway disease in ciliopathies. Combining targeted genetic disruption with 3D µCT virtual histology offers a powerful framework for comprehensive studies of human genetic variants and gene knockouts in mouse models of PCD.