Abstract
The molecular and cellular mechanisms underlying the anti-proliferative effects of preoptic regulator factor 2 (Porf-2) on neural stem cells (NSCs) remain largely unknown. Here, we found that Porf-2 inhibits the activity of ras-related C3 botulinum toxin substrate 1 (Rac1) protein in hippocampus-derived rat NSCs. Reduced Rac1 activity impaired the nuclear translocation of β-catenin, ultimately causing a repression of NSCs proliferation. Porf-2 knockdown enhanced NSCs proliferation but not in the presence of small molecule inhibitors of Rac1 or Wnt. At the same time, the repression of NSCs proliferation caused by Porf-2 overexpression was counteracted by small molecule activators of Rac1 or Wnt. By using a rat optic nerve crush model, we observed that Porf-2 knockdown enhanced the recovery of visual function. In particular, optic nerve injury in rats led to increased Wnt family member 3a (Wnt3a) protein expression, which we found responsible for enhancing Porf-2 knockdown-induced NSCs proliferation. These findings suggest that Porf-2 exerts its inhibitory effect on NSCs proliferation via Rac1-Wnt/β-catenin pathway. Porf-2 may therefore represent and interesting target for optic nerve injury recovery and therapy.
Highlights
The loss of retinal ganglion cells, caused by various diseases including optic nerve injury, results in visual dysfunction and can even cause blindness (Berkelaar et al, 1994; Quigley et al, 1995; Bien et al, 1999)
We show that preoptic regulator factor 2 (Porf-2) interacts directly with related C3 botulinum toxin substrate 1 (Rac1), regulates the nuclear localization of β-catenin, and mediates Neural stem cells (NSCs) proliferation
We found that Porf-2 downregulation significantly promoted the growth and proliferation of NSCs in culture (Figures 2, 4C,D), whereas Porf-2 overexpression led to reduced growth and proliferation (Figures 2, 4G,H)
Summary
The loss of retinal ganglion cells, caused by various diseases including optic nerve injury, results in visual dysfunction and can even cause blindness (Berkelaar et al, 1994; Quigley et al, 1995; Bien et al, 1999). Neural stem cells (NSCs) can be isolated, proliferated, genetically manipulated and differentiated and reintroduced into pathologically altered central nerve system (CNS), which have been considered a potential therapeutic approach that may restore or sustain retinal function and prevent blindness in patients with optic nerve injury (Nishida et al, 2000; Banin et al, 2006; Harvey et al, 2006; Muller et al, 2006; Bi et al, 2009; Yang et al, 2014). Poor survival and poor proliferation rate have limited the practical use of NSCs-based therapy (Lu et al, 2008; Carreira et al, 2014). Identifying molecules that can inhibit NSCs proliferation and deciphering the underlying cellular and molecular mechanisms of NSCs proliferation may help in the development of NSCs-based therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
