Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4
Graded phenotypic response to partial and complete deficiency of a brain-specific transcript variant of the winged helix transcription factor RFX4
复制标题
DOI：
10.1242/dev.00661
复制
发表时间：
2003-10-01
期刊：
影响因子：
4.6
通讯作者：
Zeldin, DC
中科院分区：
文献类型：
--
作者：
Blackshear, PJ;Graves, JP;Zeldin, DC
其中一种携带心脏特异性环氧合酶转基因的小鼠在年轻时出现头部肿胀和神经功能迅速下降，并出现明显的侧脑室和第三脑室脑积水。发现转基因插入到小鼠Rfx4基因座的内含子中。这种插入显然阻止了RFX4（RFX4_v3）的新变体转录本的表达，RFX4是翼螺旋转录因子的调节因子X家族的成员。两个等位基因的中断导致背中线脑结构形成和围产期死亡的深刻失败，大概是通过干扰下游基因的表达。一个等位基因的中断阻止了连合下器官的形成，这是一个重要的结构，对脑脊液流过Sylvius导水管很重要，并导致先天性脑积水。这些数据暗示RFX4_v3变体转录物对于早期脑发育以及连合下的发生至关重要。器官.这些发现可能与人类先天性脑积水有关，这是一种出生缺陷，每1000个新生儿中有0.6个受到影响。
One line of mice harboring a cardiac-specific epoxygenase transgene developed head swelling and rapid neurological decline in young adulthood, and had marked hydrocephalus of the lateral and third ventricles. The transgene was found to be inserted into an intron in the mouse Rfx4 locus. This insertion apparently prevented expression of a novel variant transcript of RFX4 (RFX4_v3), a member of the regulatory factor X family of winged helix transcription factors. Interruption of two alleles resulted in profound failure of dorsal midline brain structure formation and perinatal death, presumably by interfering with expression of downstream genes. Interruption of a single allele prevented formation of the subcommissural organ, a structure important for cerebrospinal fluid flow through the aqueduct of Sylvius, and resulted in congenital hydrocephalus. These data implicate the RFX4_v3 variant transcript as being crucial for early brain development, as well as for the genesis of the subcommissural. organ. These findings may be relevant to human congenital hydrocephalus, a birth defect that affects similar to0.6 per 1000 newborns.