Ubiquitin C-terminal hydrolase L1 regulates the morphology of neural progenitor cells and modulates their differentiation
ABSTRACT Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a component of the ubiquitin system, which has a fundamental role in regulating various biological activities. However, the functional role of the ubiquitin system in neurogenesis is not known. Here we show that UCH-L1 regulates the morphology of neural progenitor cells (NPCs) and mediates neurogenesis. UCH-L1 was expressed in cultured NPCs as well as in embryonic brain. Its expression pattern in the ventricular zone (VZ) changed between embryonic day (E) 14 and E16, which corresponds to the transition from neurogenesis to gliogenesis. At E14, UCH-L1 was highly expressed in the ventricular zone, where neurogenesis actively occurs; whereas its expression was prominent in the cortical plate at E16. UCH-L1 was very weakly detected in the VZ at E16, which corresponds to the start of gliogenesis. In cultured proliferating NPCs, UCH-L1 was co-expressed with nestin, a marker of undifferentiated cells. In differentiating cells, UCH-L1 was highly co-expressed with the early neuronal marker TuJ1. Furthermore, when UCH-L1 was induced in nestin-positive progenitor cells, the number and length of cellular processes of the progenitors decreased, suggesting that the progenitor cells were differentiating. In addition, NPCs derived from gad (UCH-L1-deficient) mice had longer processes compared with controls. The ability of UCH-L1 to regulate the morphology of nestin-positive progenitors was dependent on its binding affinity for ubiquitin but not on hydrolase activity; this result was also confirmed using gad-mouse-derived NPCs. These results suggest that UCH-L1 spatially mediates and enhances neurogenesis in the embryonic brain by regulating progenitor cell morphology.
- SourceAvailable from: umi.com
- [Show abstract] [Hide abstract]
ABSTRACT: The immune system is the site of various genotoxic stresses that occur during its maturation as well as during immune responses. These DNA lesions/modifications are primarily the consequences of specific physiological processes such as the V(D)J recombination, the immunoglobulin class switch recombination (CSR), and the generation of somatic hypermutations (SHMs) within Ig variable domains. The DNA lesions can be introduced either by specific factors (RAG1 and RAG2 in the case of V(D)J recombination and AID in the case of CSR and SHM) or during the various phases of cellular proliferation and cellular activation. All these DNA lesions are taken care of by the diverse DNA repair machineries of the cell. Several animal models as well as human conditions have established the critical importance of these DNA lesions/modifications and their repair in the physiology of the immune system. Indeed their defects have consequences ranging from immune deficiency to development of immune malignancy. The survey of human pathology has been highly instrumental in the past in identifying key factors involved in the generation of DNA modifications (AID for the Ig CSR and generation of SHM) or the repair of specific DNA damages (Artemis for V(D)J recombination). Defects in factors involved in the cell cycle checkpoints following DNA damage also have deleterious consequences on the immune system. The continuous survey of human diseases characterized by primary immunodeficiency associated with increased sensitivity to ionizing radiation should help identify other important DNA repair factors essential for the development and maintenance of the immune system.Advances in Immunology 02/2005; 87:237-95. DOI:10.1016/S0065-2776(05)87007-5 · 5.53 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: We initially examined the effects of apomorphine in vitro using mouse embryonic and adult neural progenitor cells. The effects of apomorphine treatment led to dose-dependent increases in the number of embryonic and adult neural progenitor cells, and dopamine D2 receptor antagonist treatment significantly reduced the increases induced by apomorphine. Next, we investigated the effects of apomorphine in vivo in the adult mouse hippocampus. The effects of single-dose apomorphine administration led to an increase of approximately 30% in the number of bromodeoxyuridine-positive cells in the dentate gyrus. Moreover, the chronic apomorphine administration induced an increase in the number of bromodeoxyuridine-positive cells by about 30%. Thus, we suggest that the stimulation of dopamine D2 receptors increases the proliferation of neural progenitor cells both in vivo and in vitro.Neuroreport 05/2007; 18(7):659-64. DOI:10.1097/WNR.0b013e3280bef9d3 · 1.64 Impact Factor