Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development

研究 Mylpf 调节的肌节形成如何影响肢体骨骼发育

基本信息

  • 批准号:
    10437165
  • 负责人:
  • 金额:
    $ 43.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Investigating how Mylpf-regulated sarcomere formation influences limb skeletal development In arthrogryposis, babies are born with at least two limbs with hand or foot showing contractures; it most commonly manifests as clubfoot, and it is found in roughly 1 in 4000 live births. Arthrogryposis causes impaired movement and can require many surgeries through a lifetime to correct. The disease is characterized by skeletal joint defects, but it is caused by impaired muscle movement in utero. We recently found that the muscle-expressed gene Mylpf is vital not only to normal actin movement, but also for muscle fiber integrity and that variants in human MYLPF cause Distal Arthrogryposis Type 1 (DA1). Mylpf protein binds to the myosin heavy chain near head region which moves actin during muscle contraction. We discovered that zebrafish mylpfa mutant larvae display a phenotype consistent with DA1, including impaired myosin activity, reduced muscle force overall, and complete fin paralysis. Surprisingly, we find that Mylpf function is needed not only for normal contraction, but also for the assembly of actin and myosin into the fundamental unit of muscle, called sarcomeres. In unpublished work we find that sarcomeres form poorly in mylpfa mutants, lacking one of two Mylpf genes, and are completely absent in mylpfa;mylpfb double mutants, which lack all Mylpf function. We hypothesize that Mylpf function prevents distal arthrogryposis by promoting association of sarcomeric components during the critical window of embryonic development when limb joints are forming. To test this hypothesis, we will (Aim 1) investigate the role of Mylpf in sarcomere assembly, (Aim 2a) investigate how the human MYLPF gene variants cause this musculo-skeletal disease, and (Aim 2b) when the skeletal defects can be corrected.
研究mylpf调控的肌节形成如何影响肢体骨骼发育

项目成果

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Jared Coffin Talbot其他文献

Stacked expression of Hand2 and Dlx mediates signaling from Edn1 to produce discrete pharyngeal arch patterning domains
  • DOI:
    10.1016/j.ydbio.2009.05.524
  • 发表时间:
    2009-07-15
  • 期刊:
  • 影响因子:
  • 作者:
    Jared Coffin Talbot;Charles B. Kimmel
  • 通讯作者:
    Charles B. Kimmel

Jared Coffin Talbot的其他文献

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{{ truncateString('Jared Coffin Talbot', 18)}}的其他基金

Motility and Guidance Signals Control Migration of Muscle Precursors
运动性和引导信号控制肌肉前体的迁移
  • 批准号:
    10557028
  • 财政年份:
    2023
  • 资助金额:
    $ 43.34万
  • 项目类别:

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