Groucho related gene 5 (GRG5) is a multifunctional protein that has been 
implicated in late embryonic and postnatal mouse development. Here, we describe 
a previously unknown role of GRG5 in early developmental stages by analyzing its 
function in stem cell fate decisions. By both loss and gain of function 
approaches we demonstrate that ablation of GRG5 deregulates the Embryonic Stem 
Cell (ESC) pluripotent state whereas its overexpression leads to enhanced 
self-renewal and acquisition of cancer cell-like properties. The malignant 
characteristics of teratomas generated by ESCs that overexpress GRG5 reveal its 
pro-oncogenic potential. Furthermore, transcriptomic analysis and cell 
differentiation approaches underline GRG5 as a multifaceted signaling regulator 
that represses mesendodermal-related genes. When ESCs exit pluripotency, GRG5 
promotes neuroectodermal specification via Wnt and BMP signaling suppression. 
Moreover, GRG5 promotes the neuronal reprogramming of fibroblasts and maintains 
the self-renewal of Neural Stem Cells (NSCs) by sustaining the activity of 
Notch/Hes and Stat3 signaling pathways. In summary, our results demonstrate that 
GRG5 has pleiotropic roles in stem cell biology functioning as a stemness factor 
and a neural fate specifier.