Cellular and Molecular NeuroscienceResearch PaperBrn-3b inhibits generation of amacrine cells by binding to and negatively regulating DLX1/2 in developing retina

During retinogenesis, the basic helix-loop-helix proneural gene math5 (atoh7) initiates the generation of the first-born neurons, retinal ganglion cells (RGCs), by activating a network of RGC transcription factors, including Brn-3b (POU4F2). Herein, we show that the expression of DLX1 and DLX2 is significantly down-regulated in math5-null retina but is markedly increased in Brn-3b-null retina. Interestingly, Brn-3b interacts with DLX1 through its homeodomain, and this interaction represses DLX1 activity. Retrovirus-mediated mis-expression of DLX1 or DLX2 dramatically increases the number of amacrine/bipolar cells and concurrently reduces rod photoreceptors. Conversely, combined ectopic expression of Brn-3b with DLX1 or DLX2 promotes the production of RGCs and inhibits amacrine cell differentiation. Thus, DLX1/2 play an essential role in cell fate selection between amacrine and RGCs. Brn-3b suppresses the role of DLX1/2 through physical interaction and biases the competent precursors toward RGC fates.

▶DLX1/2 are downstream targets of Math5 in retinal progenitor cells. ▶DLX1/2 physically bind to Brn-3b through the homeodomain. ▶Activity of DLX1 can be inhibited by the direct interaction by Brn-3b. ▶Brn-3b and DLX determines the cell fate choice between amacrine cells and RGCs.