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Transient YAP activation uncovers the neurogenic potential of proliferative mammalian Müller glia
English J Laserna1,2, Irina V Saltykova2, Benjamin M Hall2
1Genetics and Genomics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
The Hippo pathway effector YAP promotes spontaneous proliferation of Müller glia (MG), suggesting that bypassing Hippo signaling and activating YAP could enhance retinal regeneration. However, whether proliferative adult MGs retain meaningful neurogenic competence remains unclear. Here, using viral delivery of a Hippo-resistant YAP variant to wild-type adult MGs, we achieved transient YAP activation in adult MGs, inducing proliferation followed by cell-cycle withdrawal and differentiation. Intersectional genetic lineage tracing and EdU labeling, combined with transcriptomic analyses, revealed that YAP-activated MGs predominantly regenerate MGs, whereas only a subset gives rise to bipolar cell-like neurons. These results indicate that proliferative MGs acquire a state resembling that of late-stage retinal progenitors, with limited neurogenic lineage potential. We conclude that YAP-activated cell-cycle reentry inefficiently reprograms adult MGs toward photoreceptor or ganglion cell fates. These findings define the limited competence of proliferative adult MGs to contribute to neurogenic fates and provide a rigorous framework for assessing in vivo glial reprogramming strategies.
Insights
Activating YAP in Müller glia (MG) induces proliferation but primarily regenerates MGs, not diverse neurons. This suggests limited neurogenic potential in reprogrammed adult MGs for retinal repair.
Area of Science:
- Ophthalmology
- Neuroscience
- Cell Biology
Background:
- The Hippo pathway effector YAP promotes Müller glia (MG) proliferation.
- Activating YAP may enhance retinal regeneration by bypassing Hippo signaling.
- The neurogenic competence of proliferative adult MGs is not well understood.
Purpose of the Study:
- To investigate the neurogenic potential of adult MGs after YAP activation.
- To determine if YAP-activated MGs can be reprogrammed into various retinal cell types.
- To assess the feasibility of in vivo glial reprogramming for retinal regeneration.
Main Methods:
- Viral delivery of a Hippo-resistant YAP variant to adult MGs.
- Induction of transient YAP activation, proliferation, and differentiation in MGs.
- Intersectional genetic lineage tracing, EdU labeling, and transcriptomic analyses.
Main Results:
- YAP activation induced MG proliferation followed by cell-cycle withdrawal and differentiation.
- YAP-activated MGs predominantly regenerated MGs, with a subset forming bipolar cell-like neurons.
- Transcriptomic and lineage analyses revealed MGs resemble late-stage retinal progenitors with limited neurogenic potential.
Conclusions:
- YAP-activated cell-cycle reentry inefficiently reprograms adult MGs toward photoreceptor or ganglion cell fates.
- Proliferative adult MGs exhibit limited competence for generating diverse neurogenic fates.
- Findings provide a framework for evaluating in vivo glial reprogramming strategies for retinal repair.
