The Fraser complex interconnects tissue layers to support basal epidermis and osteoblast integrated morphogenesis underlying fin skeletal patterning.
The Fraser complex interconnects tissue layers to support basal epidermis and osteoblast integrated morphogenesis underlying fin skeletal patterning.
复制标题
弗雷泽复合体将组织层相互连接起来，以支持鳍骨骼图案下的基底表皮和成骨细胞整合形态发生。
DOI：
10.1101/2023.07.08.548238
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Stankunas,Kryn
中科院分区：
文献类型：
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作者：
Robbins,AmyE;Horst,SamuelG;Lewis,VictorM;Stewart,Scott;Stankunas,Kryn
弗雷泽综合征是一种罕见的多系统常染色体隐性遗传疾病，其特征是弗雷泽复合体基因丢失后上皮间质关联破坏。疾病表现和受影响的器官变化很大。并指等手指畸形很常见，但发育起源尚不清楚。我们探讨了斑马鱼弗雷泽细胞外基质复合物亚基 1 (fras1) 突变体是否能够模拟弗雷泽综合征相关的四肢骨骼图案缺陷。大约 10% 的 offras1 突变体能存活到成年，表现出引人注目的各种鳍异常，包括软骨内骨融合、异位软骨和尾鳍对称性破坏。幸存的fras1突变体的鳍通常具有较少且不分支的骨射线。fras1突变体的鳍再生至其原始大小，但具有加剧的射线分支和鳍对称缺陷。单细胞RNA-Seq分析、原位杂交和抗体染色显示再生生长过程中基底表皮中特异的弗雷泽复合物表达。 Fras1 和 Fraser Complex 成分 Frem2 沿着最远端基底表皮细胞的基底侧积累。 Frem2 的大大减少和错误定位伴随着 Fras1 infras1 突变体的损失。远端基底表皮和邻近间充质前成骨细胞之间促进射线分支的声波刺猬信号在弗雷泽复合体丢失后仍然存在。然而，fras1突变体的再生鳍表现出广泛的表皮下起泡，与紊乱的基底表皮和邻近的前成骨细胞有关。我们提出弗雷泽复合体支持的组织层粘附能够实现涉及基底表皮和成骨细胞的稳健的整合组织形态发生。此外，我们建立了斑马鱼鳍的发育和再生作为一个可访问的模型，以探索弗雷泽综合症相关的手指缺陷和上皮间质界面弗雷泽复合体功能的机制。
Fraser Syndrome is a rare, multisystemic autosomal recessive disorder characterized by disrupted epithelial-mesenchymal associations upon loss of Fraser Complex genes. Disease manifestation and affected organs are highly variable. Digit malformations such as syndactyly are common but of unclear developmental origins. We explored if zebrafishfraser extracellular matrix complex subunit 1 (fras1)mutants model Fraser Syndrome-associated appendicular skeleton patterning defects. Approximately 10% offras1mutants survive to adulthood, displaying striking and varied fin abnormalities, including endochondral bone fusions, ectopic cartilage, and disrupted caudal fin symmetry. The fins of survivingfras1mutants frequently have fewer and unbranched bony rays.fras1mutant fins regenerate to their original size but with exacerbated ray branching and fin symmetry defects. Single cell RNA-Seq analysis,in situhybridizations, and antibody staining show specific Fraser complex expression in the basal epidermis during regenerative outgrowth. Fras1 and Fraser Complex component Frem2 accumulate along the basal side of distal-most basal epidermal cells. Greatly reduced and mislocalized Frem2 accompanies loss of Fras1 infras1mutants. The Sonic hedgehog signaling between distal basal epidermis and adjacent mesenchymal pre-osteoblasts that promotes ray branching persists upon Fraser Complex loss. However,fras1mutant regenerating fins exhibit extensive sub-epidermal blistering associated with a disorganized basal epidermis and adjacent pre-osteoblasts. We propose Fraser Complex-supported tissue layer adhesion enables robust integrated tissue morphogenesis involving the basal epidermis and osteoblasts. Further, we establish zebrafish fin development and regeneration as an accessible model to explore mechanisms of Fraser Syndrome-associated digit defects and Fraser Complex function at epithelial-mesenchymal interfaces.