The Regulation of Notch Signaling in Retinal Development and Regeneration

Abstract

Purpose of review Notch signaling is an important component of retinal progenitor cell maintenance and MG specification during development, and its manipulation may be critical for allowing MG to re-enter the cell cycle and regenerate neurons in adults. In mammals, MG respond to retinal injury by undergoing a gliotic response rather than a regenerative one. Understanding the complexities of Notch signaling may allow for strategies that enhance regeneration over gliosis. Recent findings Notch signaling is regulated at multiple levels, and is interdependent with various other signaling pathways in both the receptor and ligand expressing cells. The precise spatial and temporal patterning of Notch components is necessary for proper retinal development. Regenerative species undergo a dynamic regulation of Notch signaling in MG upon injury, whereas non-regenerative species fail to productively regulate Notch. Summary Notch signaling is malleable, such that the altered composition of growth and transcription factors in the developing and mature retinas result in different Notch mediated responses. Successful regeneration will require the manipulation of the retinal environment to foster a dynamic rather than static regulation of Notch signaling in concert with other reprogramming and differentiation factors.

Biphasic Role of Tgf-β Signaling during Müller Glia Reprogramming and Retinal Regeneration in Zebrafish

“…In zebrafish, MG reprogramming leads to the induction of progenitors with stem cell-like properties, which is the pivotal step to prevent fibroblast-mediated wound closure and scar formation. Different developmentally essential pathways have been associated with MG reprogramming and retinal regeneration such as Wnt (Meyers et al, 2012;Ramachandran et al, 2011), Delta-Notch (Conner et al, 2014;Mills and Goldman, 2017), Fgf (Hochmann et al, 2012;Qin et al, 2011), and Shh signaling. However, the significance of Tgf-b signaling during retinal regeneration remained underexplored.…”

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

“…30 The Notch signaling pathway is important for both retinal development and visual function; and particularly, in lower vertebrates, it is considered to play a pivotal role during retinal regeneration. 31 In chickens, the blockade of Notch signaling with the c-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), inhibits the formation of MGPCs after injury. 15,19 Although both, GH and Notch signaling have critical actions in retinal development and neural healing after a neurotoxic injury, 9,15 a direct link between the two has not previously been demonstrated in neural tissue.…”

Rebuilding the Retina: Prospects for Müller Glial-mediated Self-repair

“…70 This requirement for increased Notch signalling in Medaka MG regeneration highlights further differences between pro-regenerative species, such as the zebrafish, and nonregenerative species, including mammals and, possibly, Medaka fish. During retinal development, the levels of Notch in RPCs determines whether they will be retained within the cell cycle or exit and differentiate; a decrease in Notch signalling is necessary for proper differentiation (See, 71 for further discussion). However, in the later stages of development the same pathway, if sustained at high levels, stimulates glial differentiation.…”