Onecut1 and Onecut2 redundantly regulate early retinal cell fates during development

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Onecut1 (Oc1) and Onecut2 (Oc2) are expressed in retinal progenitor cells, retinal ganglion cells (RGCs), and horizontal cells (HCs).
• Oc1-null mice show an 80% reduction in HCs, while Oc2-null mice show a 50% reduction in HCs, suggesting functional redundancy.

Purpose of the Study:

• To investigate the role of Oc1 and Oc2 in retinal development and explore potential functional redundancy.
• To identify downstream targets of Oc1 and Oc2 and understand their molecular mechanisms in regulating retinal cell fate.

Main Methods:

• Generation and analysis of Oc1-null, Oc2-null, and Oc1/Oc2 double-null mice.
• RNA-sequencing (RNA-Seq) expression profiling to identify downstream genes.

Main Results:

• Oc1/Oc2 double knockout retinas exhibit severe defects in early retinal cell development, including failed HC genesis, compromised cone generation, reduced RGC production (30%), and absence of starburst amacrine cells.
• Cone subtype diversification and RGC subtype composition were altered in double-null retinas.
• RNA-Seq identified downstream genes, confirming redundancy and revealing that Oc1/Oc2 factors suppress late-born rod cell production.

Conclusions:

• Oc1 and Oc2 play redundant roles in the development of multiple retinal cell types.
• These transcription factors are essential for establishing retinal progenitor cell competence for early cell fates and suppressing late cell fates.
• The findings provide insights into the regulation of cellular diversity in the retina and the central nervous system.