Zhang Donghui, Zeldin Darryl C, Blackshear Perry J
Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
J Neurosci Res. 2007 Dec;85(16):3515-22. doi: 10.1002/jnr.21356.
Regulatory factor X4 variant 3 (RFX4_v3) is a recently identified transcription factor specifically expressed in the brain. Gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/-) prevented formation of the subcommissural organ (SCO), resulting in congenital hydrocephalus, whereas interruption of two alleles (homozygous, -/-) caused fatal failure of dorsal midline brain structure formation. These mutagenesis studies implicated RFX4_v3 in early brain development as well as the genesis of the SCO. Rfx4_v3 deficiency presumably causes abnormalities in brain by altering the expression levels of many genes that are crucial for brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein, and retinoic acid pathways. RFX4_v3 might affect these critical signaling pathways in brain development. Cx3cl1, a chemokine gene highly expressed in brain, was identified as a direct target for RFX4_v3, indicating that RFX4_v3 possesses trans-acting activity to stimulate gene expression. Rfx4_v3 is highly expressed in the suprachiasmatic nucleus and might be involved in regulating the circadian clock. One haplotype in RFX4_v3 gene is linked to a higher risk of bipolar disorder, suggesting that this protein might contribute to the pathogenesis of the disease. This Mini-Review describes our current knowledge about RFX4_v3, an important protein that appears to be involved in many aspects of brain development and disease.
调节因子X4变体3（RFX4_v3）是一种最近发现的在大脑中特异性表达的转录因子。小鼠基因破坏实验表明，单个等位基因中断（杂合子，+/-）会阻止连合下器官（SCO）形成，导致先天性脑积水，而两个等位基因中断（纯合子，-/-）则会导致背侧中线脑结构形成致命性失败。这些诱变研究表明RFX4_v3参与早期脑发育以及SCO的发生。Rfx4_v3缺陷可能通过改变许多对脑形态发生至关重要的基因的表达水平而导致脑部异常，比如Wnt、骨形态发生蛋白和视黄酸信号通路中的信号成分。RFX4_v3可能会影响脑发育中的这些关键信号通路。Cx3cl1是一种在脑中高表达的趋化因子基因，被确定为RFX4_v3的直接靶点，这表明RFX4_v3具有刺激基因表达的反式作用活性。Rfx4_v3在视交叉上核中高表达，可能参与调节生物钟。RFX4_v3基因中的一个单倍型与双相情感障碍的较高风险相关，这表明这种蛋白质可能在该疾病的发病机制中起作用。本综述介绍了我们目前对RFX4_v3的认识，这是一种似乎参与脑发育和疾病诸多方面的重要蛋白质。
