1.State Key Laboratory of Virology, CAS Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China2.University of Chinese Academy of Sciences, Beijing 100049, China3.The Joint Center of Translational Precision Medicine; Guangzhou Institute of Pediatrics, Guangzhou Women and Children Medical Center, Guangzhou 510000, China
Abstract:
Human cytomegalovirus (HCMV) infection is a leading cause of birth defects, primarily affecting the central nervous system and causing its maldevelopment. As the essential downstream effector of Notch signaling pathway, Hes1, and its dynamic expression, plays an essential role on maintaining neural progenitor /stem cells (NPCs) cell fate and fetal brain development. In the present study, we reported the first observation of Hes1 oscillatory expression in human NPCs, with an approximately 1.5 hour periodicity and a Hes1 protein half-life of about 17 (17.6 ± 0.2) minutes. HCMV infection disrupts the Hes1 rhythm and down-regulates its expression. Furthermore, we discovered that depleting Hes1 protein disturbed NPCs cell fate by suppressing NPCs proliferation and neurosphere formation, and driving NPCs abnormal differentiation. These results suggested a novel mechanism linking disruption of Hes1 rhythm and down-regulation of Hes1 expression to neurodevelopmental disorders caused by congenital HCMV infection.
