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Notch pathway mutants do not equivalently perturb mouse embryonic retinal development. | LitMetric

Notch pathway mutants do not equivalently perturb mouse embryonic retinal development.

PLoS Genet

Department of Cell Biology & Human Anatomy, University of California, Davis, California, United States of America.

Published: September 2023

AI Article Synopsis

  • The study investigates how Notch signaling and its associated components influence the fate of retinal progenitor cells in the vertebrate eye by analyzing the effects of various genetic mutations in mice.
  • Researchers found that disrupting Notch signaling prevents progenitor cell growth, yet certain components like Hes1 can still function independently, highlighting a complex interaction within the pathway.
  • The results indicate that shifts in early cell fate are linked to changes in the expression of the photoreceptor factor Otx2, while Hes1 emerges as a critical point where both Notch-dependent and independent signals converge during eye development.

Article Abstract

In the vertebrate eye, Notch ligands, receptors, and ternary complex components determine the destiny of retinal progenitor cells in part by regulating Hes effector gene activity. There are multiple paralogues for nearly every node in this pathway, which results in numerous instances of redundancy and compensation during development. To dissect such complexity at the earliest stages of eye development, we used seven germline or conditional mutant mice and two spatiotemporally distinct Cre drivers. We perturbed the Notch ternary complex and multiple Hes genes to understand if Notch regulates optic stalk/nerve head development; and to test intracellular pathway components for their Notch-dependent versus -independent roles during retinal ganglion cell and cone photoreceptor competence and fate acquisition. We confirmed that disrupting Notch signaling universally blocks progenitor cell growth, but delineated specific pathway components that can act independently, such as sustained Hes1 expression in the optic stalk/nerve head. In retinal progenitor cells, we found that among the genes tested, they do not uniformly suppress retinal ganglion cell or cone differentiation; which is not due differences in developmental timing. We discovered that shifts in the earliest cell fates correlate with expression changes for the early photoreceptor factor Otx2, but not with Atoh7, a factor required for retinal ganglion cell formation. During photoreceptor genesis we also better defined multiple and simultaneous activities for Rbpj and Hes1 and identify redundant activities that occur downstream of Notch. Given its unique roles at the retina-optic stalk boundary and cone photoreceptor genesis, our data suggest Hes1 as a hub where Notch-dependent and -independent inputs converge.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10522021PMC
http://dx.doi.org/10.1371/journal.pgen.1010928DOI Listing

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