Mice Haploinsufficient for Ets1 and Fli1 Display Middle Ear Abnormalities and Model Aspects of Jacobsen Syndrome
Mice Haploinsufficient for Ets1 and Fli1 Display Middle Ear Abnormalities and Model Aspects of Jacobsen Syndrome
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DOI：
10.1016/j.ajpath.2015.03.026
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发表时间：
2015-07-01
影响因子：
6
通讯作者：
Burt, Rachel A.
中科院分区：
文献类型：
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作者：
Carpinelli, Marina R.;Kruse, Elizabeth A.;Burt, Rachel A.
E26转化特异性1（ETS 1）和朋友白血病整合1（FLI 1）是ETS家族转录因子的成员，人类中有28个。这两种基因在Jacobsen综合征中都是半合子的，Jacobsen综合征是一种11 q连续基因缺失疾病，涉及血小板减少症、面部畸形、生长和智力迟钝、心脏和其他器官畸形以及与复发性耳部感染相关的听力障碍。为了确定这些缺陷是否是因为ETS 1和FLI 1的半合子，我们表征了Ets 1和FLI 1突变等位基因杂合子小鼠的表型。Fli 1（+/-）小鼠显示轻度血小板减少症，Ets 1（+/-）Fli 1（+/-）动物也是如此。Fli 1（+/-）和Ets 1（+/-）Fli 1（+/-）小鼠也显示颅面异常，包括小中耳腔、短鼻骨和鼻骨突与软骨性鼻中隔之间的畸形界面。他们表现出听力障碍，中耳炎，融合的听小骨中耳壁，和畸形镫骨。与Fli 1（+/-）小鼠相比，Ets 1（+/-）Fli 1（+/-）小鼠的听力损伤更明显，镫骨畸形更严重，表明这些转录因子在听觉发育过程中存在部分功能冗余。我们的研究结果表明，Jacobsen综合征的短鼻、中耳炎和听力障碍可能是由于ETS 1和FLI 1的半合子。
E26 transformation-specific 1 (ETS1) and friend leukemia integration 1 (FLI1) are members of the ETS family of transcription factors, of which there are 28 in humans. Both genes are hemizygous in Jacobsen syndrome, an 11q contiguous gene deletion disorder involving thrombocytopenia, facial dysmorphism, growth and mental retardation, malformation of the heart and other organs, and hearing impairment associated with recurrent ear infections. To determine whether any of these defects are because of hemizygosity for ETS1 and FLI1, we characterized the phenotype of mice heterozygous for mutant alleles of Ets1 and Fli1. Fli1(+/-) mice displayed mild thrombocytopenia, as did Ets1(+/-)Fli1(+/-) animals. Fli1(+/-) and Ets1(+/-)Fli1(+/-) mice also displayed craniofacial abnormalities, including a small middle ear cavity, short nasal bone, and malformed interface between the nasal bone process and cartilaginous nasal septum. They exhibited hearing impairment, otitis media, fusions of ossicles to the middle ear wall, and deformed stapes. Hearing impairment was more penetrant and stapes malformations were more severe in Ets1(+/-)Fli1(+/-) mice than in Fli1(+/-) mice, indicating partial functional redundancy of these transcription factors during auditory development. Our findings indicate that the short nose, otitis media, and hearing impairment in Jacobsen syndrome are Likely because of hemizygosity for ETS1 and FLI1.