Alternative titles; symbolsMILI, MOUSE, HOMOLOG OF; MILIHGNC Approved Gene Symbol: PIWIL2Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,275,...
Alternative titles; symbols
HGNC Approved Gene Symbol: PIWIL2
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,275,313-22,357,567 (from NCBI)
PIWIL2 belongs to the Argonaute family of proteins, which function in development and maintenance of germline stem cells (Sasaki et al., 2003).
▼ Cloning and Expression
By searching databases for homologs of PIWIL1 (605571), followed by PCR of a testis cDNA library, Sasaki et al. (2003) cloned PIWIL2. Like all other Argonaute family members, PIWIL2 contains a central PAZ motif and a C-terminal PIWI motif. PCR analysis of adult and fetal tissues detected PIWIL2 only in adult testis.
Wang et al. (2001) cloned mouse Piwil2. RT-PCR detected expression only in testis and spermatogonia.
▼ Gene Function
By coimmunoprecipitation of transfected human kidney cell lysates, Sasaki et al. (2003) demonstrated that PIWIL2 associated with DICER (DICER1; 606241).
Lee et al. (2006) found enhanced expression of PIWIL2 in testicular seminomas, but not in testicular nonseminomatous tumors. PIWIL2 was also expressed in human and mouse tumors of various tissues. Overexpression of mouse Piwil2 in a fibroblast cell line increased Bclxl (600039) expression, which correlated with increased Stat3 (102582) expression and cell transformation. Piwil2 silencing via small interfering RNA suppressed Stat3 and Bclxl expression and induced apoptosis. Lee et al. (2006) concluded that PIWIL2 acts as an oncogene by inhibiting apoptosis and promoting proliferation via a STAT3/BCLXL signaling pathway.
Aravin et al. (2006) identified a novel class of small RNAs that bound Mili, the mouse homolog of PIWIL2, in male germ cells, where they accumulated at the onset of meiosis. The sequences of the more than 1,000 identified unique molecules shared a strong preference for a 5-prime uridine. Genomic mapping revealed a limited number of clusters, suggesting that these RNAs are processed from long primary transcripts. The small RNAs are 26 to 31 nucleotides in length and thus clearly distinct from the 12 to 23 nucleotides of microRNAs (miRNAs) or short interfering RNAs (siRNAs), and Aravin et al. (2006) referred to them as Piwi-interacting RNAs (piRNAs). They determined that orthologous human chromosomal regions also give rise to small RNAs with characteristics of piRNAs, but the cloned sequences were distinct. Aravin et al. (2006) concluded that identification of piRNAs provides a starting point to determine the molecular function of Piwi proteins in mammalian spermatogenesis.
A search for murine small RNAs that might program Piwi proteins for transposon suppression conducted by Aravin et al. (2007) revealed developmentally regulated piRNA loci, some of which resemble transposon master control loci of Drosophila. Aravin et al. (2007) also found evidence of an adaptive amplification loop in which Mili catalyzes the formation of piRNA 5-prime ends. Mili mutants derepress Line-1 (L1; see 151626) and intracisternal A particle and lose DNA methylation of L1 elements, demonstrating an evolutionarily conserved role for PIWI proteins in transposon suppression.
Sasaki et al. (2003) stated that by genomic sequence analysis, they mapped the PIWIL2 gene to chromosome 8p24, but this must be in error as this band does not appear on standard ideograms. The gene maps to 8p21.3. Wang et al. (2001) mapped the mouse Piwil2 gene to chromosome 14.
▼ Animal Model
To investigate the role of Piwi-catalyzed endonucleolytic activity, De Fazio et al. (2011) engineered point mutations in mice that substitute the second aspartic acid to an alanine in the DDH catalytic triad of Mili and Miwi2 (610315), generating Mili(DAH) and Miwi2(DAH) alleles, respectively. Analysis of Mili-bound piRNAs from homozygous Mili(DAH) fetal gonadocytes revealed a failure of transposon piRNA amplification, resulting in the marked reduction of piRNA bound within Miwi2 ribonuclear particles. De Fazio et al. (2011) found that Mili-mediated piRNA amplification is selectively required for LINE-1, but not intracisternal A particle, silencing. The defective piRNA pathway in Mili(DAH) mice results in spermatogenic failure and sterility. Surprisingly, homozygous Miwi2(DAH) mice are fertile, transposon silencing is established normally, and no defects in secondary piRNA biogenesis are observed. In addition, the hallmarks of piRNA amplification are observed in Miwi2-deficient gonadocytes. De Fazio et al. (2011) concluded that cycles of intra-Mili secondary piRNA biogenesis fuel piRNA amplification that is absolutely required for LINE-1 silencing.
Marchetto et al. (2013) described the generation and initial characterization of induced pluripotent stem (iPS) cells from chimpanzees and bonobos as tools to explore factors that may have contributed to great ape evolution. Comparative gene expression analysis of human and nonhuman primate iPS cells revealed differences in the regulation of long interspersed element-1 (L1) transposons. A force of change in mammalian evolution, L1 elements are retrotransposons that have remained active during primate evolution. Decreased levels of L1-restricting factors APOBEC3B (607110) and PIWIL2 in nonhuman primate iPS cells correlated with increased L1 mobility and endogenous L1 mRNA levels. Moreover, results from the manipulation of APOBEC3B and PIWIL2 levels in iPS cells supported a causal inverse relationship between levels of these proteins and L1 retrotransposition. Finally, Marchetto et al. (2013) found increased copy numbers of species-specific L1 elements in the genome of chimpanzees compared to humans, supporting the idea that increased L1 mobility in nonhuman primates is not limited to iPS cells in culture and may have also occurred in the germline or embryonic cells developmentally upstream to germline specification during primate evolution. Marchetto et al. (2013) proposed that differences in L1 mobility may have differentially shaped the genomes of humans and nonhuman primates and could have continuing adaptive significance.