LIM-Homeodomain Transcription Factor LHX4 Is Required for the Differentiation of Retinal Rod Bipolar Cells and OFF-Cone Bipolar Subtypes

Xuhui Dong,Hua Yang,Xiangtian Zhou,Xiaoling Xie,Dongliang Yu,Luming Guo,Mei Xu,Wenjun Zhang,Guoqing Liang,Lin Gan

doi:10.1016/j.celrep.2020.108144

Abstract

SUMMARYRetinal 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.

Highlights

In the retina, bipolar cells (BCs) are positioned in the inner nuclear layer (INL) between photoreceptors at the outer nuclear layer (ONL) and retinal ganglion cells (RGCs) at the ganglion cell layer (GCL)
By using a conditional knockout approach to inactivate Lhx4 in developing mouse retinas, we demonstrated that Lhx4 acts upstream of Bhlhe23, Prdm8, Fezf2, Lhx3, and other BC genes in the differentiation pathway of BCs and that Lhx4 is essential for the differentiation of rod bipolar cells (RBCs) and cone bipolar cell (CBC) subtypes and the inhibition of GABAergic amacrine cells (ACs)
LHX4 was not detected in the cells expressing PRKCA (Figures 1C, S1A, and S1B), a marker for RBCs, and a small population of ACs in adult retinas (Haverkamp et al, 2003)

Summary

Introduction

Bipolar cells (BCs) are positioned in the inner nuclear layer (INL) between photoreceptors at the outer nuclear layer (ONL) and retinal ganglion cells (RGCs) at the ganglion cell layer (GCL). Overexpression of Vsx in mouse retinas leads to an increase of BCs at the expense of rod photoreceptors (Livne-Bar et al, 2006). In mice null for the basic helix-loop-helix (bHLH) TF genes Ascl and Neurod, BCs are absent and Mu€ller glial cells are significantly increased (Hatakeyama et al, 2001; Tomita et al, 2000). Overexpression of either Ascl or Neurod together with Vsx promotes BC generation at the expense of Mu€ller glial cells, suggesting that these two classes of TFs together specify the bipolar cell fate (Hatakeyama et al, 2001). Isl, and Prdm are required for rod bipolar cell (RBC) differentiation. Mice null for Bhlhe, Isl, or Prdm lose all or most of RBCs and have a defective b-wave in electroretinogram (ERG), resembling human congenital stationary night blindness (CSNB) (Bramblett et al, 2004; Elshatory et al, 2007; Jung et al, 2015)

Results

Discussion

Conclusion