Pou3f1 orchestrates a gene regulatory network controlling contralateral retinogeniculate projections

• Published in: Cell reports (Cambridge) Vol. 42; no. 8; p. 112985
• Main Authors: Fries, Michel, Brown, Thomas W., Jolicoeur, Christine, Boulan, Benoit, Boudreau-Pinsonneault, Camille, Javed, Awais, Abram, Pénélope, Cayouette, Michel
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 29-08-2023; Elsevier
• Subjects: axon guidance; binocular; circuit; circuit development; CP: Developmental biology; CP: Neuroscience; gene network; optic nerve; optic tract; sight; stereopsis; tracing; transcriptional regulation; vision; stereopsis; tracing; circuit; optic tract; CP: Neuroscience; transcriptional regulation; gene network; CP: Developmental biology; binocular; vision; circuit development; sight; axon guidance; optic nerve
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112985

The balance of contralateral and ipsilateral retinogeniculate projections is critical for binocular vision, but the transcriptional programs regulating this process remain ill defined. Here we show that the Pou class homeobox protein POU3F1 is expressed in nascent mouse contralateral retinal ganglion cells (cRGCs) but not ipsilateral RGCs (iRGCs). Upon Pou3f1 inactivation, the proportion of cRGCs is reduced in favor of iRGCs, leading to abnormal projection ratios at the optic chiasm. Conversely, misexpression of Pou3f1 in progenitors increases the production of cRGCs. Using CUT&RUN and RNA sequencing in gain- and loss-of-function assays, we demonstrate that POU3F1 regulates expression of several key members of the cRGC gene regulatory network. Finally, we report that POU3F1 is sufficient to induce RGC-like cell production, even in late-stage retinal progenitors of Atoh7 knockout mice. This work uncovers POU3F1 as a regulator of the cRGC transcriptional program, opening possibilities for optic nerve regenerative therapies.
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•POU3F1 is expressed in postmitotic RGC precursors but downregulated in most mature RGCs•Pou3f1 loss increases production of ipsilateral RGCs at the expense of contralateral RGCs•POU3F1 represses ipsilateral determinants and activates contralateral determinants•POU3F1 promotes RGC-like cell production when misexpressed in late progenitors
Fries et al. demonstrate that POU3F1 is expressed in postmitotic retinal ganglion cell (RGC) precursors, where it represses Atoh7 and the ipsilateral determinant Zic2, while promoting expression of several contralateral determinants, leading to the generation of contralateral RGCs. This work uncovers a developmental regulator of cells involved in binocular vision.