Abstract
Müller cells may have stem cell-like capability as they regenerate photoreceptor loss upon injury in some vertebrates, but not in mammals. Indeed, mammalian Müller cells undergo major cellular and molecular changes summarized as reactive gliosis. Transforming growth factor beta (TGFβ) isoforms are multifunctional cytokines that play a central role, both in wound healing and in tissue repair. Here, we studied the role of TGFβ isoforms and their signaling pathways in response to injury induction during tissue regeneration in zebrafish and scar formation in mouse. Our transcriptome analysis showed a different activation of canonical and non-canonical signaling pathways and how they shaped the injury response. In particular, TGFβ3 promotes retinal regeneration via Smad-dependent canonical pathway upon regulation of junb gene family and mycb in zebrafish Müller cells. However, in mice, TGFβ1 and TGFβ2 evoke the p38MAPK signaling pathway. The activation of this non-canonical pathway leads to retinal gliosis. Thus, the regenerative versus reparative effect of the TGFβ pathway observed may rely on the activation of different signaling cascades. This provides one explanation of the different injury response in zebrafish and mouse retina.
Highlights
The anatomical structure of the retina and its cellular composition are highly conserved across all vertebrates (Livesey and Cepko 2001), its regenerative modalities and capacities are very different
In zebrafish, the dimension of the hyper-reflective signal started diminishing from 3 dpli, while in mouse it started increasing from the same time point (Fig. 1a, b)
While TGFβ3 is activated after injury in the zebrafish, we found TGFβ1 and TGFβ2 were activated in Müller cells in our murine model
Summary
The anatomical structure of the retina and its cellular composition are highly conserved across all vertebrates (Livesey and Cepko 2001), its regenerative modalities and capacities are very different. Teleost can fully regenerate retinal tissue upon injury (Lenkowski and Raymond 2014). The major source for endogenous retinal regeneration are Müller cells. Müller cells can rapidly dedifferentiate, proliferate, and generate progenitors that migrate to the damaged retinal layer and differentiate (Lenkowski and Raymond 2014). The activation and consequent proliferation of Müller cells in response to all forms of injury and disease, is a feature of many neurodegenerative diseases of the retina (e.g., retinitis pigmentosa, glaucoma) (Bringmann and Reichenbach 2001; Bringmann et al 2006). After injury, Müller cells generate neurotrophic factors to promote recovery
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