Germ cell nuclear factor: an orphan receptor with unexpected properties

Abstract

The orphan receptor germ cell nuclear factor (GCNF) is a member of the superfamily of nuclear receptors. During embryogenesis GCNF expression is restricted to the developing nervous system, whereas in the adult the receptor is also expressed during specific stages in maturing germ cells of the ovary and testis. Therefore GCNF may participate in the regulation of neurogenesis and reproductive functions. Binding of GCNF to the consensus element TCA[AG(G/T)TCA]₂ (conRE), to the direct repeat DNA element AGGTCAAGGTCA (DR0), and to extended half-sites such as TCAAGGTCA (XRE) has been demonstrated, but no natural GCNF target gene has been identified. However, due to an overlapping temporal expression pattern and the presence of DR0-type elements in their promoter regions, the protamine 1 and 2 genes have been proposed as potential candidates for a regulation by GCNF. Since GCNF binds as a homodimer to all three elements (conRE, DR0, and XRE) the receptor exhibits an exceptional property within the nuclear receptor superfamily. Homodimeric binding of GCNF to extended half-sites requires the presence of a novel dimerization motif located in the putative helix 3 of the GCNF ligand-binding domain (LBD). Since neither potential ligands nor heterodimerization partners or cofactors for GCNF have been identified, little is known about the mechanisms by which the receptor controls transcriptional processes. Due to the lack of a conserved transcriptional activation function 2 core motif (AF-2 AD core) in the helix 12 region of the GCNF LBD, it has been suggested that GCNF functions as a repressor of transcription. In addition, recent data suggest that the helix 12 region displays functions distinct from those in other nuclear receptors and is involved in the control of DNA binding. Together, these reports indicate that GCNF exhibits novel properties distinct from other members of the nuclear receptor superfamily.