Pbx3 deficiency results in central hypoventilation
Pbx3 deficiency results in central hypoventilation
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DOI：
10.1016/s0002-9440(10)63392-5
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发表时间：
2004-10-01
影响因子：
6
通讯作者：
Cleary, ML
中科院分区：
文献类型：
--
作者：
Rhee, JW;Arata, A;Cleary, ML
Pbx蛋白包含TALE（三个氨基酸环延伸）类同源结构域转录因子家族，其通过其形成异源寡聚DNA结合复合物的能力参与发育基因表达并在许多细胞类型中充当转录调节因子。我们在这里证明，这个家庭的一个成员，Pbx3，主要是在发展中的中枢神经系统，包括一个区域的延髓，涉及呼吸的控制，以高水平表达。Pbx3缺陷小鼠发育到足月，但在出生后几小时内死于中枢呼吸衰竭，这是由于髓质中吸气神经元的异常活动。这部分表型复制了Rnx缺陷小鼠的缺陷，Rnx是一种MetaHox同源结构域转录因子，我们在这里证明了它能够与Pbx3形成DNA结合复合物。Rnx表达在Pbx3缺陷小鼠中未受干扰，但其作为与TALE蛋白的复合物在体外增强转录的能力在Pbx3不存在的情况下受到损害。因此，Pbx3对呼吸是必不可少的，并且与其DNA结合伴侣Rnx一样，对于延髓呼吸控制机制的适当发展至关重要。Pbx3缺陷小鼠提供了先天性中枢性通气不足综合征的模型，并表明Pbx3突变可能促进这种疾病的发病机制。
Pbx proteins comprise a family of TALE (three amino acid loop extension) class homeodomain transcription factors that are implicated in developmental gene expression through their abilities to form hetero-oligomeric DNA-binding complexes and function as transcriptional regulators in numerous cell types. We demonstrate here that one member of this family, Pbx3, is expressed at high levels predominantly in the developing central nervous system, including a region of the medulla oblongata that is implicated in the control of respiration. Pbx3-deficient mice develop to term but die within a few hours of birth from central respiratory failure due to abnormal activity of inspiratory neurons in the medulla. This partially phenocopies the defect in mice deficient for Rnx, a metaHox homeodomain transcription factor, that we demonstrate here is capable of forming a DNA-binding complex with Pbx3. Rnx expression is unperturbed in Pbx3-deficient mice, but its ability to enhance transcription in vitro as a complex with TALE proteins is compromised in the absence of Pbx3. Thus, Pbx3 is essential for respiration and, like its DNA-binding partner Rnx, is critical for proper development of medullary respiratory control mechanisms. Pbx3-deficient mice provide a model for congenital central hypoventilation syndrome and suggest that Pbx3 mutations may promote the pathogenesis of this disorder.