The transcription factor MITF in RPE function and dysfunction

Ma, Xiaoyin; Li, Huirong; Chen, Yu; Yang, Juan; Chen, Huaicheng; Arnheiter, Heinz; Hou, Ling

doi:10.1016/j.preteyeres.2019.06.002

Cited by 51 publications

(32 citation statements)

References 191 publications

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“…Retinal degeneration due to photoreceptor loss is a major threat to human health as progressive vision loss severely interferes with a person's daily activities. Such photoreceptor cell loss is common to a number of degenerative eye disorders including cone dystrophy, retinitis pigmentosa (RP) and the highly prevalent age-related macular degeneration (AMD) (Ma et al, 2019;Mitchell et al, 2018;Wright et al, 2010). Each of these disorders is influenced, to various degrees, by mutations in a number of distinct genes.…”

Section: Introductionmentioning

confidence: 99%

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

Lian

Liu

et al. 2020

eLife

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Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here, we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

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Section: Introductionmentioning

confidence: 99%

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

Lian

Liu

et al. 2020

eLife

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“…Through MITF regulation, Cse1l mediates cell survival, proliferation, melanogenesis, and metastasis [ 42 , 43 , 44 ]. PAX6 and MITF have been shown to interact in a network arbitrating the counterbalanced developmental programs of retinogenesis and presumptive RPE melanogenesis [ 40 , 45 , 46 ]. These systems must be intricately synchronized to facilitate proper development of the eye.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in Cse1l Disrupts Brain and Eye Development with Specific Effects on Pax6 Expression

Blizzard

Menke

Patel

et al. 2021

JDB

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Forward genetics in the mouse continues to be a useful and unbiased approach to identifying new genes and alleles with previously unappreciated roles in mammalian development and disease. Here, we report a new mouse allele of Cse1l that was recovered from an ENU mutagenesis screen. Embryos homozygous for the anteater allele of Cse1l display a number of variable phenotypes, with craniofacial and ocular malformations being the most obvious. We provide evidence that Cse1l is the causal gene through complementation with a novel null allele of Cse1l generated by CRISPR-Cas9 editing. While the variability in the anteater phenotype was high enough to preclude a detailed molecular analysis, we demonstrate a very penetrant reduction in Pax6 levels in the developing eye along with significant ocular developmental phenotypes. The eye gene discovery tool iSyTE shows Cse1l to be significantly expressed in the lens from early eye development stages in embryos through adulthood. Cse1l has not previously been shown to be required for organogenesis as homozygosity for a null allele results in very early lethality. Future detailed studies of Cse1l function in craniofacial and neural development will be best served with a conditional allele to circumvent the variable phenotypes we report here. We suggest that human next-generation (whole genome or exome) sequencing studies yielding variants of unknown significance in CSE1L could consider these findings as part of variant analysis.

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“…64 The transcription factor icrophthalmia-associated transcription factor (MITF) is highly expressed in RPE and other neural crest-derived tissues, and mutations in this protein cause a variety of phenotypes in mice, most notably microphthalmia and retinal degeneration. 65 Coculture models were created to study early retinal organogenesis, particularly the question of how apical-basal polarity is attained.…”

Section: Models Of Differentiation and Developmentmentioning

confidence: 99%

Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine

Ghareeb

Lako

Steel

2020

Stem Cells Translational Medicine

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Stem cell‐derived retinal organoids offer the opportunity to cure retinal degeneration of wide‐ranging etiology either through the study of in vitro models or the generation of tissue for transplantation. However, despite much work in animals and several human pilot studies, satisfactory therapies have not been developed. Two major challenges for retinal regenerative medicine are (a) physical cell‐cell interactions, which are critical to graft function, are not formed and (b) the host environment does not provide suitable queues for development. Several strategies offer to improve the delivery, integration, maturation, and functionality of cell transplantation. These include minimally invasive delivery, biocompatible material vehicles, retinal cell sheets, and optogenetics. Optimizing several variables in animal models is practically difficult, limited by anatomical and disease pathology which is often different to humans, and faces regulatory and ethical challenges. High‐throughput methods are needed to experimentally optimize these variables. Retinal organoids will be important to the success of these models. In their current state, they do not incorporate a representative retinal pigment epithelium (RPE)‐photoreceptor interface nor vascular elements, which influence the neural retina phenotype directly and are known to be dysfunctional in common retinal diseases such as age‐related macular degeneration. Advanced coculture techniques, which emulate the RPE‐photoreceptor and RPE‐Bruch's‐choriocapillaris interactions, can incorporate disease‐specific, human retinal organoids and overcome these drawbacks. Herein, we review retinal coculture models of the neural retina, RPE, and choriocapillaris. We delineate the scientific need for such systems in the study of retinal organogenesis, disease modeling, and the optimization of regenerative cell therapies for retinal degeneration.

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The transcription factor MITF in RPE function and dysfunction

Cited by 51 publications

References 191 publications

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

KIT ligand protects against both light-induced and genetic photoreceptor degeneration

A Novel Mutation in Cse1l Disrupts Brain and Eye Development with Specific Effects on Pax6 Expression

Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine

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