ESCRT-I protein UBAP1 controls ventricular expansion and cortical neurogenesis via modulating adherens junctions of radial glial cells.

Intricate cerebral cortex formation is orchestrated by the precise behavior and division dynamics of radial glial cells (RGCs). Endocytosis functions in the recycling and remodeling of adherens junctions (AJs) in response to changes in RGC activity and function. Here, we show that conditional disruption of ubiquitin-associated protein 1 (UBAP1), a component of endosomal sorting complex required for transport (ESCRT), causes severe brain dysplasia and prenatal ventriculomegaly. UBAP1 depletion disrupts the AJs and polarity of RGCs, leading to failure of apically directed interkinetic nuclear migration. Accordingly, UBAP1 knockout or knockdown results in reduced proliferation and precocious differentiation of neural progenitor cells. Mechanistically, UBAP1 regulates the expression and surface localization of cell adhesion molecules, and ß-catenin over-expression significantly rescues the phenotypes of Ubap1 knockdown in vivo. Our study reveals a critical physiological role of the ESCRT machinery in cortical neurogenesis by regulating AJs of RGCs.

Stress-Activated Protein Kinase JNK Modulates Depression-like Behaviors in Mice.

Stress is considered as a major cause of depression. C-Jun N-terminal kinase (JNK) is a member of the stress-induced mitogen activated protein (MAP) kinase family which is often activated through phosphorylation. Clinical studies and animal experiments have found that abnormal phosphorylation/activation of JNK exists in the occurrence of various psychiatric diseases. Recently, several studies linked JNK kinase activity to depression. However, whether excessive activation of JNK activity is directly responsible for the occurrence of depression and the underlying mechanisms remain unclear. Here, we constructed a conditional transgenic mouse which is specifically expressing MKK7-JNK1 (CAJNK1) in the central nervous system. CAJNK1 mice showed activation of JNK and lead to depression-like behavior in mice. Transcriptome analysis indicates reduced expression of synaptic-associated genes in CAJNK1 mice brains. Consistently, we found abnormal dendritic spine development and PSD95 downregulation in CAJNK1 hippocampal neurons. Our studies provide compelling evidence that activation of JNK as an intrinsic factor leading to depression-like behavior in mice provides direct clues for targeting the JNK activity as a potential therapeutic strategy for depression.

Downregulation of CDC25C in NPCs Disturbed Cortical Neurogenesis.

Cell division regulators play a vital role in neural progenitor cell (NPC) proliferation and differentiation. Cell division cycle 25C (CDC25C) is a member of the CDC25 family of phosphatases which positively regulate cell division by activating cyclin-dependent protein kinases (CDKs). However, mice with the Cdc25c gene knocked out were shown to be viable and lacked the apparent phenotype due to genetic compensation by Cdc25a and/or Cdc25b. Here, we investigate the function of Cdc25c in developing rat brains by knocking down Cdc25c in NPCs using in utero electroporation. Our results indicate that Cdc25c plays an essential role in maintaining the proliferative state of NPCs during cortical development. The knockdown of Cdc25c causes early cell cycle exit and the premature differentiation of NPCs. Our study uncovers a novel role of CDC25C in NPC division and cell fate determination. In addition, our study presents a functional approach to studying the role of genes, which elicit genetic compensation with knockout, in cortical neurogenesis by knocking down in vivo.