USP11 is required for neural fate determination
Date Issued
2015
Date
2015
Author(s)
Chiang, Shang-Yin
Abstract
In the ubiquitin-proteasome pathway, ubiquitin is conjugated to the target proteins by ubiquitin E3 ligases and removed by deubiquitinating enzymes (DUBs). Although a number of E3 ligases are known to play roles in neural development, little is known about the function of DUBs in this process. Previous studies in our laboratory revealed that the repression of USP11, a USP family of DUB, contributes to the effect of Notch on potentiating the stemness properties of glioma-initiating cells. Given the importance of Notch signaling in controlling neural stem/progenitor cells self-renewal and differentiation, we investigated the expression and function of USP11 during neurogenesis. By in situ hybridization, we found that USP11 is most abundantly expressed in developing central nervous system, including cells located in cortical plate of neocortex in E12.5, E14.5 and E17.5 of mouse embryos. Using an ex vivo neural differentiation protocol of mouse embryonic stem (ES) cells, we found that USP11 expression is up-regulated during ES cells differentiation into neural progenitor cells (NPC) and further up-regulated during NPC differentiation into neurons. Consistent with this finding, overexpression of USP11 in ES cells leads to a precocious NPC and neuron differentiation, as evident by earlier induction of NPC and neuron markers. In contrast, depletion of USP11 attenuates NPC differentiation and impairs neuron differentiation. Interestingly, overexpression of a catalytically inactive mutant of USP11 does not promote NPC and neuron differentiation, but leads to an induction of glial cell fate. These ex vivo data were further verified by in vivo studies with an in uterus gene delivery technique. Together, our data identify a critical role of USP11 in neural fate determination. Future study will aim to identify USP11 substrate that mediates this function.
Subjects
neural fate
differentiation
mouse ES cells
Type
thesis
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