Table 2.
Key Notch signaling findings in retinal development, growth, and regeneration
| Signaling component | Organism | Key finding | Reference |
|---|---|---|---|
| Development | |||
| Notch1 | Mouse | Maintains progenitor cell state and promotes cell proliferation | Furukawa et al., 2000 |
| Promotes MG formation | Jadhav et al., 2006a | ||
| Inhibits photoreceptor fate | Jadhav et al., 2006b | ||
| Dll4/Jagged1 and Fringe proteins | Mouse | Fringe glycosylation of Notch enhances Dll4 binding and weakens Jagged1 binding to regulate retinal angiogenesis | Benedito et al., 2009 |
| Mindbomb | Zebrafish | RanBP9 antagonistically regulates Mindbomb, which influences her4 expression | Yoo et al., 2017 |
| Numb | Mouse | Promotes early-stage cell-cycle progression and late-stage terminal asymmetric cell divisions | Kechad et al., 2012 |
| ADAM10 | Mouse | Activates Notch signaling to promote progenitor cell proliferation | Toonen et al., 2016 |
| Sfrp1 and Sfrp2 bind and downregulate ADAM10 activity | Esteve et al., 2011a | ||
| Psen1 | Zebrafish | Knockdown reduces eye size | Nery et al., 2017 |
| Rbpj | Mouse | Interacts with four CSL binding sites to repress Atoh7 expression in Notch-dependent and independent pathways | Miesfeld et al., 2018 |
| Hes1 | Mouse | Hes1 expressed in all progenitor cells | Riesenberg et al., 2018 |
| Hes1 suppresses Hes5 transcription | Nelson et al., 2011 | ||
| Hes5 | Hes5 expressed in subsets of progenitors and in differentiating ganglion cells | ||
| Hes5 expressed in adult MG | |||
| Hes5 | Mouse | Hes5-dependent gliogenesis requires Lhx2 | de Melo et al., 2016 |
| Dll1/Dll4-Notch1-Rbpj-Hes1 | Mouse | Promotes retinal progenitor cell proliferation and inhibits retinal ganglion cell neurogenesis | Riesenberg et al., 2009 Maurer et al., 2014 |
| Ciliary Marginal Zone (persistent neurogenesis) | |||
| Notch1a, Notch1b, DeltaA, DeltaD, Her2, Her4, Her6 | Zebrafish | Expression restricted to proliferative CMZ cells during retinal development and in the adult retina | Bernardos et al., 2005 Raymond et al., 2006 Taylor et al., 2015 |
| Regeneration | |||
| Notch3, DeltaB | Zebrafish | Notch3 expressed in MG, deltaB expressed in neurons; knockdown of either stimulates MG proliferation | Campbell et al., 2021 |
| γ-Secretase | Zebrafish | γ-Secretase inhibition increased/induced MG proliferation, which was reversed by Notch1a ICD expression | Wan et al., 2012 |
| MG proliferation induced by γ-secretase inhibition was enhanced by TNFα | Conner et al., 2014 | ||
| Notch1 and γ-secretase | Postnatal chick | Notch1 and signaling components upregulated after retinal damage | Hayes et al., 2007 |
| γ-Secretase inhibition prohibited MG dedifferentiation and proliferation at early regeneration stages and increased newly generated neurons at late regeneration stages | |||
| Notch1 expression is upregulated in proliferating MG in insulin/FGF2-treated retinas | Ghai et al., 2010 | ||
| γ-Secretase inhibition blocked FGF2-induced proliferation | |||
| Notch signaling/Fgf8a | Zebrafish | Forced Fgf8a expression increases Notch signaling and suppresses MG proliferation in older tissue but inhibits Notch and stimulates MG proliferation in young tissue | Wan and Goldman, 2017 |
| Dll4 | dll4 and hey1 expression is suppressed after injury, but forced Fgf8a after injury increases expression of both | ||
| Hey1 | |||
| Notch signaling/Tgfb signaling | Zebrafish | Tgfb3 acts upstream of Notch signaling to suppress injury-induced MG reprogramming and proliferation | Lee et al., 2020 |
| Dll4 | Forced Tgfb3 increases dll4 and hey1 expression | ||
| Hey1 | |||
| Her4 | Pharmacological inhibition of Tgfb increases her4.1 expression and decreases NPC proliferation at late stages | Sharma et al., 2020 | |
| Her4 | Zebrafish | her4 expressed in slowly proliferating MG of undamaged adult retina and in proliferating cells in ONL & INL following light damage | Wilson et al., 2016 |
| GABA inhibition induces MG proliferation and her4:RFP expression | Rao et al., 2017 | ||
| Represses lin28a expression; two Her4 binding sites on lin28a promoter | Mitra et al., 2018 | ||
| Late inhibition of her4.1 increases NPC proliferation | |||
| Mycb inhibits her4.1 expression with Hdac1 in cells neighboring NPCs | Mitra et al., 2019 | ||
| Stimulation of Regeneration in Mammals | |||
| Notch1, Delta1, Hes1 | Rat | Expression increased in neurotoxin-damaged retina | Das et al., 2006 |
| γ-Secretase | γ-Secretase inhibition decreased cell cycle regulators cyclinA and cyclinD1 | ||
| Jag1 | Mouse | Jag1-activation of Notch signaling with Wnt activation induced MG cell cycle reentry and rod photoreceptor differentiation in culture, retinal explant, and in S334ter rat in vivo | Del Debbio et al., 2010 |
| Hes1 | Rat | Notch activates MG by inhibiting p27Kip1 expression | Del Debbio et al., 2016 |
| γ-Secretase | Mouse | γ-Secretase inhibition with forced Ascl1a and Lin28 expression inefficiently stimulated MG proliferation in mouse retina | Elsaeidi et al., 2018 |
ADAM: A disintegrin and metalloprotease 10; CMZ: ciliary marginal zone; Dll: delta-like; Her: hairy-related; Hes: hairy and enhancer of split; Hey: Hes-related; Jag: jagged; MG: Müller glia; Psen: presenilin.