The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis
The del22q11.2 candidate gene Tbx1 regulates branchiomeric myogenesis
复制标题
DOI：
10.1093/hmg/ddh304
复制
发表时间：
2004-11-15
影响因子：
3.5
通讯作者：
Papaioannou, VE
中科院分区：
文献类型：
--
作者：
Kelly, RG;Jerome-Majewska, LA;Papaioannou, VE
咽弓的形成和重塑在颅面发育中起着核心作用。TBX1编码一个含有t -box的转录因子，是del22q11.2 （DiGeorge或velo-cardio-facial）综合征的主要候选基因，其特征是颅面缺陷、胸腺发育不全、心血管异常、velo-咽功能不全和骨骼肌强张。Tbx1在咽中胚层表达，产生头颈部的支状骨骼肌。尽管已知颅面肌发育的遗传控制涉及不同于躯干的通路，但branbranial muscle genesis的调控仍然是一个谜。本研究表明，Tbx1突变小鼠的分支肌发育受到严重干扰。在缺乏Tbx1的情况下，Myf5和MyoD在咽中胚层不能正常激活。表达转录抑制因子荚膜蛋白和MyoR基因的未指定前体细胞存在于Tbx1突变胚胎的下颌弓中。这些前体细胞中Myf5和MyoD的零星激活导致在发育后期随机存在或不存在发育不全的下颌弓源性肌肉。Tbx1也是Tlx1和Fgf10在咽中胚层中正常表达所必需的，此外还需要下颌弓神经嵴细胞模式的正确表达。因此，Tbx1调节branbraneric mygenesis的发生，并控制正常的下颌弓发育，包括强健的肌生成决定基因的转录激活。虽然在Tbx1（+/-）小鼠中未检测到分支肌生成异常，但Tbx1水平降低可能导致del22q11.2患者的咽张力低下。
Formation and remodeling of the pharyngeal arches play central roles in craniofacial development. TBX1, encoding a T-box-containing transcription factor, is the major candidate gene for del22q11.2 (DiGeorge or velo-cardio-facial) syndrome, characterized by craniofacial defects, thymic hypoplasia, cardiovascular anomalies, velopharyngeal insufficiency and skeletal muscle hypotonia. Tbx1 is expressed in pharyngeal mesoderm, which gives rise to branchiomeric skeletal muscles of the head and neck. Although the genetic control of craniofacial muscle development is known to involve pathways distinct from those operational in the trunk, the regulation of branchiomeric myogenesis has remained enigmatic. Here we show that branchiomeric muscle development is severely perturbed in Tbx1 mutant mice. In the absence of Tbx1, the myogenic determination genes Myf5 and MyoD fail to be normally activated in pharyngeal mesoderm. Unspecified precursor cells expressing genes encoding the transcriptional repressors Capsulin and MyoR are present in the mandibular arch of Tbx1 mutant embryos. Sporadic activation of Myf5 and MyoD in these precursor cells results in the random presence or absence of hypoplastic mandibular arch-derived muscles at later developmental stages. Tbx1 is also required for normal expression of Tlx1 and Fgf10 in pharyngeal mesoderm, in addition to correct neural crest cell patterning in the mandibular arch. Tbx1 therefore regulates the onset of branchiomeric myogenesis and controls normal mandibular arch development, including robust transcriptional activation of myogenic determination genes. While no abnormalities in branchiomeric myogenesis were detected in Tbx1(+/-) mice, reduced TBX1 levels may contribute to pharyngeal hypotonia in del22q11.2 patients.