Handling Editor: Steve Wilson
ABSTRACT
Multipotent retinal progenitor cells (RPCs) generate various cell types in a precise chronological order, but how exactly cone photoreceptor production is restricted to early stages remains unclear. Here, we show that the POU-homeodomain factors Pou2f1/Pou2f2, the homologs of Drosophila temporal identity factors nub/pdm2, regulate the timely production of cones in mice. Forcing sustained expression of Pou2f1 or Pou2f2 in RPCs expands the period of cone production, whereas misexpression in late-stage RPCs triggers ectopic cone production at the expense of late-born fates. Mechanistically, we report that Pou2f1 induces Pou2f2 expression, which binds to a POU motif in the promoter of the rod-inducing factor Nrl to repress its expression. Conversely, conditional inactivation of Pou2f2 in RPCs increases Nrl expression and reduces cone production. Finally, we provide evidence that Pou2f1 is part of a cross-regulatory cascade with the other temporal identity factors Ikzf1 and Casz1. These results uncover Pou2f1/2 as regulators of the temporal window for cone genesis and, given their widespread expression in the nervous system, raise the possibility of a general role in temporal patterning.
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Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: A.J., P.M., M.C.; Methodology: A.J., P.M., M.C.; Formal analysis: A.J., P.M.; Investigation: A.J., P.M., S.L., K.K., M.K., A.G.-C.; Resources: R.B., R.R.A., M.C.; Writing - original draft: A.J.; Writing - review & editing: P.M., R.B., R.R.A., M.C.; Supervision: R.B., R.R.A., M.C.; Project administration: R.B., R.R.A., M.C.; Funding acquisition: R.B., R.R.A., M.C.
Funding
This work was funded by grants from the Canadian Institutes of Health Research (FDN-159936) and Fighting Blindness Canada (to M.C.), the Fondation Brain Canada/Krembril Foundation (to M.C. and R.B.), as well as the UK Medical Research Council, the European Research Council and RP Fighting Blindness (to R.A.). A.J. holds a PhD scholarship from Fonds de Recherche du Québec – Santé. M.C. is an Emeritus Scholar from the Fonds de Recherche du Québec – Santé and holds the Gaëtane and Roland Pillenière Chair in Retina Biology from the Institut de recherches cliniques de Montréal Foundation.
Supplementary information
Supplementary information available online at https://dev.biologists.org/lookup/doi/10.1242/dev.188730.supplemental
- Received January 23, 2020.
- Accepted August 19, 2020.
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