Foxp1 Coordinates Early Temporal Identity and Neurogenic Progression in Retinal Progenitors

Neural diversity depends on both the temporal competence of progenitors to generate particular cell types and their progression into a neurogenic state. How these distinct features of progenitor development are mechanistically coordinated remains poorly understood. Here, we identify Foxp1 as a dual function transcriptional regulator that couples early progenitor identity to neurogenic progression in the developing retina. By defining its direct transcriptional targets, we show that Foxp1 coordinates complementary regulatory programs: it sustains early competence by activating early-stage retinal progenitor genes and repressing late temporal factors, while promoting neurogenic progression through activation of the proneural factors Atoh7 and Neurog2 . We establish a cis-regulatory mechanism linking these functions: Foxp1 activates Atoh7 through its remote shadow enhancer, and deletion of this enhancer prevents Foxp1-dependent induction of Atoh7 and retinal ganglion cell (RGC) production. We further reveal that Neurog2 partially compensates for loss of Atoh7 function. This coordinated early progenitor program is temporally restricted by progressive silencing of Foxp1 , involving sequential deposition of H2AK119ub1 followed by H3K27me3 at a distal conserved silencer essential for its repression. Together, these findings establish a mechanistic link between temporal competence and neurogenic progression, revealing how a shared transcriptional regulator coordinates progenitor identity with neuronal production through distinct cis-regulatory elements.

Temporal competence and neurogenic progression are distinct features of neural progenitor development, yet how they are mechanistically coordinated remains poorly understood. We identify Foxp1 as a transcriptional regulator that couples early progenitor identity to neurogenic progression in the developing retina. Foxp1 activates early competence genes, represses late temporal factors, and directly activates proneural regulators. Functional dissection of cis-regulatory elements establishes an enhancer requirement for Foxp1-dependent neuronal production and a silencer requirement for repression of Foxp1 itself. These findings reveal how coordinated transcriptional activation and repression connect progenitor competence to neuronal differentiation, providing a mechanistic framework for understanding the temporal control of neural cell diversity.