GDF-3 (previously called Vgr-2) is a TGF-beta superfamily member belonging to the growth/differentiation factor family. GDF-3 is expressed in undifferentiated embryonic stem (ES) cells, white adipose tissue and the brain. The 366 amino acid (aa) mouse GDF-3 contains a 22 aa signal sequence, a 230 aa propeptide and a 114 aa mature protein that contains one potential N-glycosylation site. The mature region contains a cysteine-knot structure that is conserved throughout family members. However, it lacks the fourth cysteine which is responsible for the formation of an inter-molecular disulfide bond, so GDF-3 may exist as a non-covalent homodimer. Mature human GDF-3 shares 83%, 83% aa sequence identity with mouse and rat GDF-3. Most of GDF-3 is present as the uncleaved prepro form. The uncleaved and the mature forms both appear to have activity, but that activity may differ. All forms can oppose BMPs. In ES cells, inhibition of BMP2 signaling by GDF-3 maintains pluripotency. GDF-3 also influences early cell fate decisions, for example, deletion of mouse GDF-3 produces defects in the anterior visceral endoderm of the pre-gastrulation embryo. GDF-3 cooperates with GDF-1 in embryogenesis, and the mature protein has nodal-like activity. Although GDF family members signal through BMP receptors (ALK1, 2, 3 and 6), which activate Smads 1, 5 and 8, GDF-3 signaling through ALK4 and ALK7, which activate Smads 2 and 3, has also been reported. In adipocytes, GDF-3 is induced by a high fat diet, promoting adipogenesis and obesity.
