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

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

doi:10.1016/j.celrep.2020.108144

Cited by 17 publications

(15 citation statements)

References 45 publications

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“…Based on previous reports, LHX4 is expressed in BCs and PRs of both mouse and chicken retinas. In mice, LHX4 is transiently expressed in the rod BCs and RPs of the developing retina and persistently expressed in the CPs, ON-cone BCs, and four subtypes of OFF-cone BCs (type 2, 3a, 3b, and 4) of the adult retina [34][35][36] . Buenaventura et al found that the conservation expression of LHX4 in early CPs of mouse and chicken retinas is a new marker of early CPs 37 .…”

Section: Discussionmentioning

confidence: 99%

“…Of note, no effect occurred on the differentiation of OFF-BCs (marked by vsx1), rod BCs (marked by PKCα and bhlhe23), and apoptosis (marked by activated-Caspase3) in the retina. In mice, Dong et al found that Lhx4 CKO (conditional knockout) results in the loss of rod BCs, rod-connecting BCs, and AII ACs, and a visual defect resembling the human CSNB (congenital stationary night blindness) 34 . Together, these findings demonstrate that Lhx4 plays an important role in vertebrate retinal development.…”

Section: Discussionmentioning

confidence: 99%

“…33 . In the mouse retina, Dong et al found the expression of VSX2 is not changed in the early retina but decreased through apoptosis in Lhx4 null mice at the later stages 34 . Zebrafish vsx2 mRNA contains 5 exons; the primer pair used above is located in the E1 and E4.…”

Section: Discussionmentioning

confidence: 99%

“…Lhx3 and Isl2 are associated with enhanced maturation of PRs in the retina, particularly when their expression is impeded 31 . LHX4 is essential for the development of the pituitary, spinal motoneurons, and retina [32][33][34] . During retinal development, Lhx4 is expressed in the PRs and BCs of INL in the retina of mouse and chicken [35][36][37][38] .…”

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confidence: 99%

“…During retinal development, Lhx4 is expressed in the PRs and BCs of INL in the retina of mouse and chicken [35][36][37][38] . It is crucial in regulating the subtype-specific development of rod BCs and cone BCs in the mouse retina 34 . However, no reports have been published on the expression and function of Lhx4 during zebrafish retinal development.…”

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confidence: 99%

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LIM Homeobox 4 (lhx4) regulates retinal neural differentiation and visual function in zebrafish

Guo

Wang

et al. 2021

Sci Rep

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LIM homeobox 4 (LHX4) is expressed in the photoreceptors (PRs) of the outer nuclear layer (ONL) and bipolar cells (BCs) of the inner nuclear layer (INL) in mouse and chicken retina. It regulates the subtype-specific development of rod BCs and cone BCs in the mouse retina. However, no report has been published on its expression and function in the zebrafish retina. In this study, we assessed the expression of Lhx4 using in situ hybridization (ISH) technique and explored its role in zebrafish (Danio rerio) retinal development via morpholino (MO) technology. We found that the expression of lhx4 in the zebrafish retina begins 48 h post-fertilization (hpf) and is continuously expressed in the ONL and INL. A zebrafish model constructed with lhx4 knockdown in the eyes through vivo-MO revealed that: lhx4 knockdown inhibits the differentiation of Parvalbumin+ amacrine cells (ACs) and Rhodopsin+ rod photoreceptors (RPs), enhances the expression of visual system homeobox 2 (vsx2); and damages the responses of zebrafish to light stimulus, without affecting the differentiation of OFF-BCs and rod BCs, and apoptosis in the retina. These findings reveal that lhx4 regulates neural differentiation in the retina and visual function during zebrafish embryonic development.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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LIM Homeobox 4 (lhx4) regulates retinal neural differentiation and visual function in zebrafish

Guo

Wang

et al. 2021

Sci Rep

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Generation of Sigmar1 conditional knockout mouse using CRISPR‐Cas9 gene targeting

Huang

Xiao

Xie

et al. 2022

Genesis

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Summary The Sigma 1 receptor (SIGMAR1) is a transmembrane protein located in the mitochondria‐associated endoplasmic reticulum membrane, and plays an important role in cell survival as a pluripotent modulator of a variety of signaling pathways related to neurodegeneration. Though SIGMAR1 is a potential target for neurodegenerative diseases, the specific role of SIGMAR1 in different tissue and cell types remains unclear. Here we reported the generation of Sigmar1 conditional knockout (Sigmar1loxP) mice using CRISPR‐Cas9 method to insert loxP sites into the 5′‐ and 3′‐untranslated regions of Sigmar1. We showed that the insertion of loxP sequences did not affect the expression of Sigmar1 and that Sigmar1loxP/loxP mice exhibited no detectable visual defects compared with wild‐type mice at the early adult stage. By crossing Sigmar1loxP mice with retina‐specific Six3‐Cre and ubiquitous CMV‐Cre mice, we confirmed the deletion of Sigmar1 coding regions of exons 1–4, and the retina‐specific and global loss of SIGMAR1 expression, respectively. Thus, Sigmar1loxP mice provide a valuable tool for unraveling the tissue and cell‐type‐specific role of Sigmar1.

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Lhx4 surpasses its paralog Lhx3 in promoting the differentiation of spinal V2a interneurons

Renaux,

Baudouin,

Marchese

et al. 2024

Cell. Mol. Life Sci.

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Paralog factors are considered to ensure the robustness of biological processes by providing redundant activity in cells where they are co-expressed. However, the specific contribution of each factor is frequently underestimated. In the developing spinal cord, multiple families of transcription factors successively contribute to differentiate an initially homogenous population of neural progenitors into a myriad of neuronal subsets with distinct molecular, morphological, and functional characteristics. The LIM-homeodomain transcription factors Lhx3, Lhx4, Isl1 and Isl2 promote the segregation and differentiation of spinal motor neurons and V2 interneurons. Based on their high sequence identity and their similar distribution, the Lhx3 and Lhx4 paralogs are considered to contribute similarly to these processes. However, the specific contribution of Lhx4 has never been studied. Here, we provide evidence that Lhx3 and Lhx4 are present in the same cell populations during spinal cord development. Similarly to Lhx3, Lhx4 can form multiproteic complexes with Isl1 or Isl2 and the nuclear LIM interactor NLI. Lhx4 can stimulate a V2-specific enhancer more efficiently than Lhx3 and surpasses Lhx3 in promoting the differentiation of V2a interneurons in chicken embryo electroporation experiments. Finally, Lhx4 inactivation in mice results in alterations of differentiation of the V2a subpopulation, but not of motor neuron production, suggesting that Lhx4 plays unique roles in V2a differentiation that are not compensated by the presence of Lhx3. Thus, Lhx4 could be the major LIM-HD factor involved in V2a interneuron differentiation during spinal cord development and should be considered for in vitro differentiation of spinal neuronal populations.

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

Cited by 17 publications

References 45 publications

LIM Homeobox 4 (lhx4) regulates retinal neural differentiation and visual function in zebrafish

LIM Homeobox 4 (lhx4) regulates retinal neural differentiation and visual function in zebrafish

Generation of Sigmar1 conditional knockout mouse using CRISPR‐Cas9 gene targeting

Lhx4 surpasses its paralog Lhx3 in promoting the differentiation of spinal V2a interneurons

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