A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition

Autoři: Chudong Wu aff001;  Jean-François Boisclair Lachance aff002;  Michael Z. Ludwig aff003;  Ilaria Rebay aff001
Působiště autorů: Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, Illinois, United States of America aff001;  Department of Human Genetics, McGill University, Montreal, Quebec, Canada aff002;  Department of Ecology and Evolution, University of Chicago, Chicago, Illinois, United States of America aff003;  Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, United States of America aff004
Vyšlo v časopise: A context-dependent bifurcation in the Pointed transcriptional effector network contributes specificity and robustness to retinal cell fate acquisition. PLoS Genet 16(11): e1009216. doi:10.1371/journal.pgen.1009216
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009216


Spatiotemporally precise and robust cell fate transitions, which depend on specific signaling cues, are fundamental to the development of appropriately patterned tissues. The fidelity and precision with which photoreceptor fates are recruited in the Drosophila eye exemplifies these principles. The fly eye consists of a highly ordered array of ~750 ommatidia, each of which contains eight distinct photoreceptors, R1-R8, specified sequentially in a precise spatial pattern. Recruitment of R1-R7 fates requires reiterative receptor tyrosine kinase / mitogen activated protein kinase (MAPK) signaling mediated by the transcriptional effector Pointed (Pnt). However the overall signaling levels experienced by R2-R5 cells are distinct from those experienced by R1, R6 and R7. A relay mechanism between two Pnt isoforms initiated by MAPK activation directs the universal transcriptional response. Here we ask how the generic Pnt response is tailored to these two rounds of photoreceptor fate transitions. We find that during R2-R5 specification PntP2 is coexpressed with a closely related but previously uncharacterized isoform, PntP3. Using CRISPR/Cas9-generated isoform specific null alleles we show that under otherwise wild type conditions, R2-R5 fate specification is robust to loss of either PntP2 or PntP3, and that the two activate pntP1 redundantly; however under conditions of reduced MAPK activity, both are required. Mechanistically, our data suggest that intrinsic activity differences between PntP2 and PntP3, combined with positive and unexpected negative transcriptional auto- and cross-regulation, buffer first-round fates against conditions of compromised RTK signaling. In contrast, in a mechanism that may be adaptive to the stronger signaling environment used to specify R1, R6 and R7 fates, the Pnt network resets to a simpler topology in which PntP2 uniquely activates pntP1 and auto-activates its own transcription. We propose that differences in expression patterns, transcriptional activities and regulatory interactions between Pnt isoforms together facilitate context-appropriate cell fate specification in different signaling environments.

Klíčová slova:

Cloning – DNA transcription – Drosophila melanogaster – Eyes – Homozygosity – MAPK signaling cascades – Photoreceptors – Transcriptional control


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