Gonadotropin‐Regulated Testicular RNA Helicase (GRTH/DDX25): A Multifunctional Protein Essential for Spermatogenesis

Abstract

Male germ cell maturation is governed by the expression of specific protein(s) in a precise temporal sequence during development. Gonadotropin-regulated testicular RNA helicase (GRTH/DDX25), a member of the Glu-Asp-Ala-Glu (DEAD)-box protein family, is a testis-specific gonadotropin/androgen-regulated RNA helicase that is present in germ cells (meiotic spermatocytes and round spermatids) and Leydig cells. GRTH is essential for completion of spermatogenesis as a posttranscriptional regulator of relevant genes during germ cell development. Male mice lacking GRTH are sterile with spermatogenic arrest due to failure of round spermatids to elongate, where striking structural changes and reduction in size of chromatoid bodies are observed. GRTH also plays a central role in preventing germ cell apoptosis. In addition to its inherent helicase unwinding/adenosine triphosphatase activities, GRTH binds to specific mRNAs as an integral component of ribonuclear protein particles. As a shuttle protein, GRTH transports target mRNAs from nucleus to the cytoplasm for storage in chromatoid bodies of spermatids, where they await translation during spermatogenesis. GRTH is also associated with polyribosomes to regulate target gene translation. The finding of a missense mutation associated with male infertility, where its expression associates with loss of GRTH phosphorylation, supports the relevance of GRTH to human germ cell development. We conclude that the mammalian GRTH/DDX25 is a multifunctional RNA helicase that is an essential regulator of spermatogenesis and is highly relevant for studies of male infertility and contraception.