Germ cell nuclear factor is a transcriptional repressor essential for embryonic development

Abstract

GCNF is an orphan member of the nuclear receptor superfamily. The nuclear receptor superfamily is a large superfamily of transcription factors, the majority of which are designated as orphan receptors because their ligands and functions are currently unknown. GCNF (Germ Cell Nuclear Factor) is so named because of its restricted expression pattern in the adult. In the testis, GCNF is expressed only in the post meiotic round spermatids. Likewise in the ovary, GCNF's expression is restricted to the growing oocyte. To date nothing is known of GCNF's putative ligand; however, much is known about its physiological function through the use of gene targeting. Inactivation of the GCNF gene showed that it was essential for normal embryonic development. In addition to being expressed in the germ cells of the adult, it is expressed widely throughout the embryo after gastrulation. Significant strides have also been made in understanding GCNF's mechanism of action using molecular biology. The DNA binding properties of GCNF have been investigated and its response element identified. GCNF binds as a homodimer to a direct repeat element with zero nucleotides between the reiterated sequence AGGTCA. GCNF target genes have been identified that contain this DR0 element in their promoters. Such genes as Protamines 1 and 2 and Oct4 are regulated by GCNF through this element. GCNF has been shown to be a repressor of the protamine and Oct4 genes. GCNF's repression function has been shown to be mediated by interaction with the co-repressors N-CoR and SMRT in the absence of ligand. Our current efforts are to explore GCNF function in the adult germ cells using tissue specific gene targeting to specifically knock out the GCNF gene in oocytes and spermatogenic cells. In addition, efforts are being made to identify the endogenous ligand that regulates GCNF's transcriptional properties.