Vrille Gene

''Vrille'' (vri) is a bZIP transcription factor found on chromosome 2 in ''Drosophila melanogaster''. Vrille mRNA and protein product (VRI) oscillate predictably on a 24-hour timescale and interact with other circadian clock genes to regulate circadian rhythms in ''Drosophila''. It is also a regulator in embryogenesis; it is expressed in multiple cell types during multiple stages in development, coordinating embryonic dorsal/ventral polarity, wing-vein differentiation, and ensuring tracheal integrity. It is also active in the embryonic gut but the precise function there is unknown. Mutations in ''vri'' alter circadian period and cause circadian arrhythmicity and developmental defects in ''Drosophila''.

Discovery

Helene George and Regine Terracol discovered the first ''vrille'' alleles (''vri'' and ''vri'') in 1997 by EMS-mutagenesis assay and found their products to be transcription factors involved in embryogenesis. Justin Blau elucidated additional "vrille" implications in 1999 while screening for clock-controlled genes in ''Drosophila'' heads that responded to PER/TIM heterodimers.

Function

Circadian

The current model of the Drosophila circadian oscillator is composed of two interlocking transcription/translation negative feedback loops. One loop consists of ''per'', ''tim'', ''clk'', ''cyc'', and their mRNA and protein products. In this loop, the PER/TIM heterodimer is a repressor for the CLK/CYC complex while the CLK/CYC complex serves as an activator and transcription factor for ''per'' and ''tim''. ''Vrille'' is activated by the CLK/CYC complex and encodes a repressor of CLK transcription. The second regulatory loop is composed of ''vri'', ''pdp1'', ''clk'', and their mRNA and protein products. ''Vrille'' is activated by the CLK/CYC complex and encodes a repressor of CLK transcription. High levels of CLK/CYC activate the transcription of ''Vrille'' mRNA to increase protein production, leading to transcriptional repression of ''clk'' which ultimately reduces the concentration of CLK/CYC complexes. Lastly, PDP1 protein, a bZIP transcription factor, serves as an activator of ''clk'' transcription and peaks 3–6 hours after the VRI protein peak and, together with VRI, regulate daily rhythms in CLK protein.

Non-Circadian

''Vrille'' acts as an enhancer of ''decapentaplegic (dpp)'' and ''easter,'' genes critical to the development of dorsal/ventral axis in the process of regional differentiation during ''Drosophila'' embryogenesis. Likewise, it can act as an enhancer of ''dpp'' mutations. ''Easter'' is involved in initiating a protease cascade that activates the ''dorsal'' gene, resulting in repression of ''dpp'' in the ventral portion of the embryo during early fly development. The mechanism by which ''vrille'' affects the ''dpp'' pathway is still unknown.

mRNA analysis and bioinformatic analysis have suggested that ''vrille'' is involved in the regulatory networks leading to cardiac senescence. In addition, overexpression of ''vri'' has led to heart dysfunctions, while a loss of function significantly reduces age-related cardiac dysfunction as a result of oxidative stress reduction

Induction of ''vri'' in ''Drosophila'' eye precursor cells, the underdeveloped cells that will become cells of the eye, both reduces the number of ommatidia while simultaneously altering their internal structures. Overexpression of ''vri'' causes anti-proliferative effects in processes vital for limb generation, as well as abnormal phenotypes in salivary glands and internal organs. Lastly, it has been postulated that ''vri'' affects these processes by interacting with genes involved in the production of cytoskeleton although the exact process is still unknown

Homologs

The closest mammalian homolog to ''vri'' is the transcriptional regulator E4BP4 (NFIL3). Although the consensus binding site for ''vri'' has not yet been determined, its bZIP domain does share >85% homology with the protein sequence of E4BP4, and it does recognize the E4BP4 site. E4BP4 represses promoter activity in ''per1'', ''per2'', and osteoblasts, suggesting its role as a negative regulator complex of mammalian circadian clocks. It transcriptionally activates interleukin-3, and is implicated in apoptotic pathways. No other mammalian homologs have been discovered.

The crustacean ''Daphnia magna'' co-opts its ''vri'' ortholog for activating the ''doublesex'' sex-determination gene, a task accomplished by ''tra'' in flies. It recognizes the ''dsx1'' enhancer sequence CGTTATA:ACATTGTTAT.

References

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Drosophila melanogaster genes