Fndc5 knockdown significantly decreased the expression of neurotrophins and their respective receptors during neural differentiation of mouse embryonic stem cells.

Fibronectin type III domain-containing-5 (Fndc5) is a trans-membrane protein which is involved in a variety of cellular events including neural differentiation of mouse embryonic stem cells (mESCs) as its knockdown and overexpression diminishes and facilitates this process, respectively. However, downstream targets of Fndc5 in neurogenesis are still unclear. Neurotrophins including NGF, BDNF, NT-3, and NT-4 are the primary regulators of neuronal survival, growth, differentiation, and repair. These biomolecules exert their actions through binding to two different receptor families, Trk and p75NTR. In this study, considering the fact that neurotrophins and their receptors play crucial roles in neural differentiation of ESCs, we sought to evaluate whether knockdown of Fndc5 decreased neural differentiation of mESCs by affecting the neurotrophins and their receptors expression. Results showed that at neural progenitor stage, the mRNA and protein levels of BDNF, Trk, and p75NTR receptors decreased following the Fndc5 knockdown. In mature neural cells, still, the expression of Trk and p75NTR receptors at mRNA and protein levels and BDNF and NGF expression only at protein levels showed a significant decrease in Fndc5 knockdown cells compared to control groups. Taken together, our results suggest that decreased efficiency of neural differentiation following the reduction of Fndc5 expression could be attributed to decreased levels of NGF and BDNF proteins in addition to their cognate receptors.