DDX25 (DEAD (Asp-Glu-Ala-Asp) box helicase 25)

	Genomic organization of the Human GRTH gene. Exons presented by boxes. The positions of the translation initiation ATG and termination TGA codon are indicated. Conserved domains of DEAD-box family of the RNA helicase are presented above its respective exon.
Description	Human GRTH gene contains 12 exons and all but one of its conserved helicase motifs are contained within single exon (Tsai-Morris et al., 2004). Motif ARG-D resides in exon 10/11.
Transcription	The GRTH gene belongs to the TATA-less/non-initiator class (Tsai-Morris et al., 2004). A single transcript of 1,6 Kb is expressed in the testis (Tang et al., 1999). Gonadotropin-induced androgen increases cause autocrine stimulation of GRTH gene transcription in Leydig cells through a non-classical half-site element residing at -827/-822 5' from the initiation codon (Tang et al., 1999; Tsai-Morris et al., 2010; Villar et al., 2012). The induction of the GRTH gene expression in germ cells (meiotic spermatocytes, round and elongated spermatids) presumbably results from paracrine actions of androgen through cognate receptors in Sertoli cells (adjacent to germinal cells).
Pseudogene	One related pseudo DDX25 (LOC100421309) was found in chromosome 5.

Description	GRTH contains three ATG in frame codons with the potential for generation of multiple protein species (61/56, 48/43 and 33 kDa) (Sheng et al., 2003). The 61/56 kDa proteins are the major species observed in the human testis (Tang et al., 1999; Tsai-Morris et al., 2007). GRTH 56- and 61-kDa species are present in nucleus and cytoplasm (Sheng et al., 2006), respectively. Based on the mouse model, the 56 kDa nuclear species interacts with CRM1 and participates in mRNA transport in the human testis and the phosphorylated 61 kDa species associates with mRNAs at polysomal sites and also within the Chromatoid Body of round spermatids.
Expression	GRTH (484 aa) is highly expressed in the testis: somatic (Leydig cells) and germinal (meiotic spermatocytes, round spermatids and elongated spermatids) cells (Sheng et al., 2003; Tsai-Morris, et al., 2004). GRTH is genetically close to DBP5/DDX19b (63% overall aa homology) involved in mRNA export (Schmitt et al., 1999).
Localisation	GRTH is localized in the nucleus and at cytoplasmic sites in polyribosomes and the Chromatoid Body (CB) of round spermatids (Tsai-Morris et al., 2004; Sheng et al., 2006; Sato et al., 2010; Tsai-Morris et al., 2012).
Function	GRTH is a multifunctional protein essential for completion of spermatogenesis as a post-transcriptional regulator of relevant genes during germ cells development (Tsai-Morris et al., 2004; Sheng et al., 2006; Dufau and Tsai-Morris, 2007; Tsai-Morris et al., 2010). It contains ATPase activity (ATP/Mg dependent), and is a bi-directional RNA helicase. As a translational regulator it participates in the in vitro and in vivo translation of RNA templates. GRTH is a shuttling protein that exports germ cell specific RNA as mRNP particles from nucleus to cytoplasm via the CRM1-dependent pathway. A specific set of testicular gene transcripts, including those of chromatin-remodeling proteins (Tp1 and Tp2, Prm1 and PRM2), cytoskeletal structural proteins (Fsc1/Odf1) and tACE are associated with GRTH protein. GRTH also selectively binds mRNAs of pro-apoptotic and anti-apoptotic genes, the death receptor and proteins involved in the NF-kB pathways to mediate anti-apoptotic regulation (Gutti et al., 2008). GRTH is required to maintain the structural integrity of the chromatoid body (storage/processing organelle of mRNAs that contains members of the small miRNA RISC-complex) during spermatogenesis (Sato et al., 2010). GRTH also participates in the regulation of microRNA biogenesis in germ cells (Dai et al., 2011) and associates with polyribosome for translational initiation of target genes. In Leydig cells, GRTH prevents overstimulation of gonadotropin-induced androgen pathway by promoting degradation of StAR protein (Fukushima et al., 2011).
	Model of GRTH action in male germ cells during development (derived from mouse studies). 56 kDa GRTH species enters the nucleus (1), where it binds messages and associates with CRM1 (2) as mRNP complex to export messages through nuclear pores via the CRM1 pathway to the cytoplasm (3a) and to the chromatoid body (CB), either directly (via nuclear pores adjacent to or associated with the CB) (3b) or indirectly via the cytoplasmic route (4b). It is phosphorylated at cytoplasmic sites, and participates in translation at polyribosomes (4a). In the CB, messages are potentially regulated via si/mi/pi RNA pathway (5a and b). Stored messages are subsequently translated in polyribosomes (4a and 6) at specific times during spermatogenesis.

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