Ephrin-A2 and-A3 are negative regulators of the regenerative potential of Müller cells

Background In a previous study, we demonstrated that ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in ephrin-A2 and -A3 （A2＋A3＋） displayed active ongoing neurogenesis throughout the brain, and mice deficient in ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of MOiler cells is influenced by the absence of ephrin-A2 and -A3. Methods We assessed the retinal and MOiler cell expression of ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary MOiler cells derived from wild-type and A2＋A3＋ mice in a defined culture medium that enables trans-differentiation of Mu11er cells into retinal neurons. To evaluate proliferating MOiler cells in vivo, we injected 5＇-ethylnyl-2-deoxiuridine （EdU） intraperitoneally to adult mice. Results Expression of ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in MOiler cells. MOiler cells of A2＋A3＋ mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Mu11er cells of A2＋A3＋ mice trans-differentiated and became recoverin＋ and β-Ⅲ-tublin＋ in the culture than those from wild type mice. Strikingly, an increased number of EdU＋ retinal cells was detected in the retinas of adult A2＋A3＋ mice as compared with wild-type mice. Conclusions Ephrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Mu11er cells. Manipulating ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.

Intrinsic determinants of optic nerve regeneration

Objective To review the functions of these intracellular signals in their regulation of retinal ganglion cell （RGC） axon regeneration. Data sources Relevant articles published in English or Chinese from 1970 to present were selected from PubMed. Searches were made using the terms ＂intrinsic determinants, axon regeneration, RGC, optic nerve regeneration, and central nervous system axon regeneration.＂ Study selection Articles studying the mechanisms controlling RGC and central nervous system （CNS） axon regeneration were reviewed. Articles focusing on the intrinsic determinants of axon regeneration were selected. Results Like other CNS neurons of mammals, RGCs undergo a developmental loss in their ability to grow axons as they mature, which is a critical contributing factor to the failure of nerve regeneration and repair after injury. This growth failure can be attributed, at least in part, by the induction of molecular programs preventing cellular overgrowth and termination of axonal growth upon maturation. Key intracellular signals and transcription factors, including B cell lymphoma/leukemia 2, cyclic adenine monophosphate, mammalian target of rapamycin, and Kr^Jppel-like transcription factors, have been identified to play central roles in this process. Conclusions Intense effort and substantial progress have been made to identify the various intrinsic growth pathways that regulate RGC axon regeneration. More work is needed to elucidate the mechanisms of and the interrelationship between the actions of these factors and to successfully achieve regeneration and repair of the severed RGC axons.