A deficiency of maternal thyroid hormones (THs) during pregnancy may have severe 
impacts on fetal brain development. However, the cellular targets of THs and 
their underlying mechanisms are still unclear. In this study, we found that 
maternal hypothyroidism during pregnancy in mice inhibited neurogenesis in the 
embryonic telencephalon and caused learning and memory impairment in the 
offspring. To explore the underlying mechanisms, we treated cultured mouse 
embryonic neural stem cells (eNSCs) with a physiological level of 3, 5, 
3'-triiodo-L-thyronine (T3). We found that T3 promoted the neuronal 
differentiation of eNSCs, while inhibiting astrocytic differentiation. In 
addition, the proliferation and maintenance of eNSCs were inhibited by T3. 
Furthermore, the TH receptor alpha 1 (TRα1) was detected in the eNSCs both in 
vivo and in vitro. Silencing TRα1 protein expression with specific siRNA 
eliminated the effects of T3 on eNSCs. We also found that T3 decreased STAT3 
phosphorylation and STAT3-DNA binding activity through TRα1. The over expression 
of STAT3 attenuated the promotive effects of T3 on neuronal differentiation of 
eNSCs. Taken together, these results suggest that T3 promotes the neuronal 
differentiation of eNSCs by inhibiting STAT3 signaling activity through TRα1 and 
contributes to early neurogenesis in the embryonic telencephalon. Our studies 
reveal the physiological effects of TH in regulating eNSCs differentiation and 
suggest that eNSCs are one of the major cellular targets in the central nervous 
system by which TH influences early brain development. These findings also 
provide new insights into the mechanisms of neurological deficits caused by TH 
deficiency during embryogenesis.