Regulatory factor X4 variant 3: A transcription factor involved in brain development and disease

Abstract

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. Keywords regulatory factor X; hydrocephalus; midline; brain development Regulatory factor X (RFX) members belong to the winged-helix subfamily of helix-turn-helix transcription factors, which share a highly conserved 76-amino-acid DNA binding domain (DBD) that is distinct from any other DBD (Gajiwala et al., 2000). These proteins regulate the expression of their target genes by binding to symmetrical "X-box" consensus sequences (Gajiwala et al., 2000). RFX family members have been identified in a broad range of

RFX3 governs growth and beating efficiency of motile cilia in mouse and controls the expression of genes involved in human ciliopathies

“…For example, Rfx3 is expressed more strongly in the brain whereas Rfx2 is expressed strongly in the kidney (Reith et al, 1994). Rfx4 also exhibits a specific expression pattern (Blackshear et al, 2003;Zhang et al, 2007). The differential expression patterns of RFX transcription factors might help to fine tune ciliogenesis in different cell types.…”

Functional Specialization of Sensory Cilia by an RFX Transcription Factor Isoform

“…In mammalian genomes, genes with alternative promoters are common (Davuluri et al 2008). Mammalian RFXs have alternative isoforms, with RFX3 encoding eight (Aftab et al 2008) and RFX4 encoding six (Zhang et al 2007). Similar to the case for daf-19, RFX3 regulates two categories of genes: those involved in ciliary assembly and in ciliary motility (El Zein et al 2009).…”

“…Similar to the case for daf-19, RFX3 regulates two categories of genes: those involved in ciliary assembly and in ciliary motility (El Zein et al 2009). Rfx4_v3 is a novel brain-specific isoform, which was identified on the basis of mutant phenotype of transgene inserted into an intron (Zhang et al 2007), which is reminiscent of daf-19m identification, based on n4132 mutant phenotypes. RFX TFs bind to the X-box motif, 4 and 5. which is common in the genome.…”

Overexpression of Drosophila Rfx3 Induces Apoptosis and Interferes with Differentiation of Photoreceptor Cells

“…RFX5, the most divergent mammalian member, regulates major histocompatibility class II gene expression and mutations in it results in the bare lymphocyte syndrome [17]. In addition, RFX4 has been implicated in dorsal patterning of brain development in mice and may participate in circadian rhythm regulation in humans [18][19][20][21]. dRFX2 is also reported to be involved in cell cycle progression and regulation of apoptosis.…”