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.

Ubiquitin C-Terminal Hydrolase-L1 Activity Induces Polyubiquitin Accumulation in Podocytes and Increases Proteinuria in Rat Membranous Nephropathy

“…11,40 In addition, UCH-L1 stabilizes the level of monoubiquitin by direct binding to monoubiquitin in neurons. 13,41 In the present study, UCH-L1 overexpression and knock-down in cultured podocytes resulted in higher and lower monoubiquitin levels, respectively. In rats, inhibition of UCH-L1 hydrolase activity lowered glomerular monoubiquitin in PHN and normal rats.…”

“…11 Biochemically, UCH isoforms process precursors of free ubiquitin and recycle ubiquitin from degraded substrates. 12 Several biological effects of UCH-L1 are based on its ability to bind to and stabilize monoubiquitin 13 and to perform ubiquitin ligase activity at Lys63. 14 UCH-L1 is associated with neurodegenerative disorders such as Parkinson's and Alzheimer's diseases.…”

Trim11 modulates the function of neurogenic transcription factor Pax6 through ubiquitin–proteosome system

“…Also, targeted mutation of UBR1 and UBR2, encoding two E3 ubiquitin ligases in the N-end rule pathway, causes severe impairment of neurogenesis . Furthermore, ubiquitin C-terminal hydrolase L1 influences the morphology of neural progenitor cells and modulates their differentiation (Sakurai et al 2006). In this study, we present evidence that Trim11 could repress Pax6-dependent neurogenesis in primary cortical cultures as well as in vivo in the developing cortex by mediating Pax6 degradation via the UPS.…”

The Tumor Suppressor UCHL1 Forms a Complex with p53/MDM2/ARF to Promote p53 Signaling and Is Frequently Silenced in Nasopharyngeal Carcinoma

“…Ubiquitination analysis indeed showed that UCHL1 promoted the deubiquitination of p14 ARF and p53 and, meanwhile, the ubiquitination of MDM2, thus elucidating the molecular mechanism of the activation of p53 signaling by UCHL1. However, whether UCHL1 mediate these effects through its two opposite enzymatic activities (50), E3 ligase and hydrolase activity, needs to be explored further. Our results also revealed another mechanism of UCHL1 acting as a tumor suppressor gene, that is, through the induction of apoptosis.…”