Notch1 inhibits neurite outgrowth in postmitotic primary neurons

Notch plays an important role in cell fate decisions in uncommitted prolife rative cells, including neurogenesis, but is believed to not have a role in postmitotic cells. We have shown previously that Notch1 is highly expresse d in embryonal mouse and human brain, but surprisingly it continues to be e xpressed at low levels in the adult brain. The function of Notch1 in postmi totic neurons in mammals is unknown. To better understand the potential rol e of Notch1 in mature central nervous system neurons we studied the effect of Notch1 transfection on neurite outgrowth in primary neocortex hippocampa l neurons. Transfection at two days in vitro with full length Notch1 inhibi ted neurite outgrowth. Transfection at five to six days in vitro, after neu rite outgrowth was established, led to apparent regression of neurites. The se effects were enhanced when truncated constitutively active forms of Notc h1 were introduced. Co-transfection with Numb, a physiological inhibitor of Notch, blocked Notch's effect on neurite outgrowth. We also examined wheth er Notch1 could activate C-promoter binding factor (CBF1) transcription fac tor using C-promoter binding factor-luciferase constructs, and demonstrated that this signal transduction pathway is present and can be activated in p ostmitotic neurons. Our results show that in postmitotic neurons Notch1 influences neurite morp hology, and can activate its native signal transduction pathway. These data strongly suggest that Notch1 may play a physiologically important role in the central nervous system beyond neurogenesis. (C) 1999 IBRO. Published by Elsevier Science Ltd.