Retinal bipolar cells (BCs) connect with photoreceptors and relay visual information to retinal ganglion cells (RGCs). Retina-specific deletion of Lhx4 in mice results in a visual defect resembling human congenital stationary night blindness. This visual dysfunction results from the absence of rod bipolar cells (RBCs) and the loss of selective rod-connecting cone bipolar cell (CBC) subtypes and AII amacrine cells (ACs). Inactivation of Lhx4 causes the apoptosis of BCs and cell fate switch from some BCs to ACs, whereas Lhx4 overexpression promotes BC genesis. Moreover, Lhx4 positively regulates Lhx3 expression to drive the fate choice of type 2 BCs over the GABAergic ACs. Lhx4 inactivation ablates Bhlhe23 expression, whereas overexpression of Bhlhe23 partially rescues RBC development in the absence of Lhx4. Thus, by acting upstream of Bhlhe23, Prdm8, Fezf2, Lhx3, and other BC genes, Lhx4, together with Isl1, could play essential roles in regulating the subtype-specific development of RBCs and CBCs.

视网膜双极细胞 (BC) 与光感受器连接并将视觉信息传递给视网膜神经节细胞 (RGC)。小鼠中Lhx4的视网膜特异性缺失会导致类似于人类先天性静止性夜盲症的视觉缺陷。这种视觉功能障碍是由于缺乏视杆双极细胞 (RBC) 和选择性视杆连接锥双极细胞 (CBC) 亚型和 AII 无长突细胞 (AC) 的缺失造成的。Lhx4的失活导致 BCs 的凋亡和细胞命运从一些 BCs 转变为 ACs，而Lhx4过表达促进 BCs 的发生。此外，Lhx4正向调节Lhx3表达以驱动 2 型 BCs 对 GABAergic ACs 的命运选择。Lhx4失活消除了Bhlhe23的表达，而Bhlhe23的过表达在Lhx4缺失的情况下部分挽救了红细胞的发育。因此，通过作用于Bhlhe23、Prdm8、Fezf2、Lhx3和其他 BC 基因的上游，Lhx4与Isl1一起在调节 RBCs 和 CBCs 的亚型特异性发育中发挥重要作用。