In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw
In vivo zebrafish morphogenesis shows Cyp26b1 promotes tendon condensation and musculoskeletal patterning in the embryonic jaw
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DOI：
10.1371/journal.pgen.1007112
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发表时间：
2017-12-01
期刊：
影响因子：
4.5
通讯作者：
Eberhart, Johann K.
中科院分区：
文献类型：
--
作者：
McGurk, Patrick D.;Swartz, Mary E.;Eberhart, Johann K.
不同组织的综合发育产生功能性的、移动的脊椎动物肌肉骨骼系统。然而，驱动肌肉、肌腱和骨骼整合的遗传学和细胞相互作用却知之甚少。在脊椎动物的头部，神经嵴细胞（颅腱的来源）会像四肢和躯干组织中的腱一样，形成发育中的肌肉，但这种形成模式的机制尚不清楚。从一个向前的遗传筛选，我们确定cyp26b1是至关重要的腹侧咽弓的肌肉骨骼整合，特别是在下颌舌骨交界处的第一和第二弓肌肉互连。使用延时共聚焦分析，我们详细介绍了野生型和cyp26b1突变斑马鱼的肌肉骨骼整合。在野生型鱼类中，成腱细胞与伸长的肌肉并列存在，并在离散的肌肉附着部位凝聚。在没有cyp26b1的情况下，成腱细胞以正常的数量产生，但不能在腹弓内凝聚成新生肌腱，随后，肌肉投射到异位区域。这些异位肌纤维最终与异位肌腱标记物表达相关。遗传镶嵌分析表明，神经嵴细胞需要Cyp26b1的功能，适当的肌肉骨骼发育。使用抑制剂，我们发现，Cyp26的功能是需要在一个短的时间窗口，重叠成腱细胞冷凝的动态窗口。然而，cyp26b1的表达在很大程度上限于成腱细胞凝聚之间的区域在这段时间。我们的研究结果表明，RA的降解，这以前未描述的神经嵴细胞的人口是至关重要的，以促进凝聚相邻的scxa表达成腱细胞，这些凝聚随后需要适当的肌肉骨骼整合。
Integrated development of diverse tissues gives rise to a functional, mobile vertebrate musculoskeletal system. However, the genetics and cellular interactions that drive the integration of muscle, tendon, and skeleton are poorly understood. In the vertebrate head, neural crest cells, from which cranial tendons derive, pattern developing muscles just as tendons have been shown to in limb and trunk tissue, yet the mechanisms of this patterning are unknown. From a forward genetic screen, we determined that cyp26b1 is critical for musculoskeletal integration in the ventral pharyngeal arches, particularly in the mandibulohyoid junction where first and second arch muscles interconnect. Using time-lapse confocal analyses, we detail musculoskeletal integration in wild-type and cyp26b1 mutant zebrafish. In wild-type fish, tenoblasts are present in apposition to elongating muscles and condense in discrete muscle attachment sites. In the absence of cyp26b1, tenoblasts are generated in normal numbers but fail to condense into nascent tendons within the ventral arches and, subsequently, muscles project into ectopic locales. These ectopic muscle fibers eventually associate with ectopic tendon marker expression. Genetic mosaic analysis demonstrates that neural crest cells require Cyp26b1 function for proper musculoskeletal development. Using an inhibitor, we find that Cyp26 function is required in a short time window that overlaps the dynamic window of tenoblast condensation. However, cyp26b1 expression is largely restricted to regions between tenoblast condensations during this time. Our results suggest that degradation of RA by this previously undescribed population of neural crest cells is critical to promote condensation of adjacent scxa-expressing tenoblasts and that these condensations are subsequently required for proper musculoskeletal integration.