Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone.

Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.

Down-regulation of LHPP in cervical cancer influences cell proliferation, metastasis and apoptosis by modulating AKT.

Cervical cancer is a leading severe malignancy throughout the world. Though various pathologies associated with cervical cancer progression have been demonstrated, further study is still necessary to reveal the tumorigenesis of cervical cancer. The protein histidine phosphatase LHPP is reported as a tumor suppressor. Histidine phosphorylation, also known as hidden phosphoproteome, is a poorly characterized post-translational modification of proteins. LHPP is evolutionarily conserved from worm to human. In the present study, we discovered that LHPP expression levels were lower in human cervical cancer tumors than that in adjacent normal tissue samples. LHPP expression levels were also reduced in several cervical cancer cell lines. Further, LHPP over-expression reduced the cell proliferation, migration and invasion, associated with the change of p53 and metastasis signaling pathways. Moreover, over-expressing LHPP markedly induced apoptosis in human cervical cancer cells via promoting the cleaved Caspse-3 and PARP. Importantly, we found that LHPP over-expression blocked AKT activation. Elevating AKT activity could abolish the role of LHPP over-expression in reducing cell proliferation and metastasis, as well as in inducing apoptotic response. Moreover, suppressing p53 expression with its inhibitor of PFTα abrogated the activity of LHPP to impede cell proliferation and metastasis, and to trigger apoptosis. AKT phosphorylation also restrained p53 expression levels in cervical cancer cells. In vivo, the anti-cervical cancer effects of LJPP were verified, which were also via the repression of cell proliferation and metastasis, and the induction of apoptosis. Therefore, LHPP could be considered as an effective candidate to develop effective therapeutic strategy against cervical cancer development.

ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development.

Zinc-finger E-box binding homeobox 1 (Zeb1) is a key regulator of epithelial-mesenchymal transition and cancer metastasis. Mutation of ZEB1 is associated with human diseases and defective brain development. Here we show that downregulation of Zeb1 expression in embryonic cortical neural progenitor cells (NPCs) is necessary for proper neuronal differentiation and migration. Overexpression of Zeb1 during neuronal differentiation, when its expression normally declines, blocks NPC lineage progression and disrupts multipolar-to-bipolar transition of differentiating neurons, leading to severe migration defects and subcortical heterotopia bands at postnatal stages. ZEB1 regulates a cohort of genes involved in cell differentiation and migration, including Neurod1 and Pard6b. The interaction between ZEB1 and CTBP2 in the embryonic cerebral cortex is required for ZEB1 to elicit its effect on the multipolar-to-bipolar transition, but not its suppression of Neurod1. These findings provide insights into understanding the complexity of transcriptional regulation during neuronal differentiation.

Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells.

During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs. This in turn diminished the embryonic origin of postnatal NSCs, resulting in loss of adult NSCs and defective V-SVZ regeneration. VCAM1 affects the NSC fate by signaling through its intracellular domain to regulate ß-catenin signaling in a context-dependent manner. Our findings provide new insight on how stem cells in the embryo are preserved to meet the need for growth and regeneration.