Transcript isoforms of Reep6 have distinct functions in the retina

Liang, Qingnan; Wu, Nathaniel; Zaneveld, Smriti Agrawal; Liu, Hehe; Fu, Shangyi; Wang, Keqing; Bertrand, Renae Elaine; Wang, Jun; Li, Yumei; Chen, Rui

doi:10.1093/hmg/ddab157

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…Isoforms produced by alternative splicing might have different functions. For example, two splice variants of receptor expression-enhancing protein 6 gene have distinct functions in the retina [ 62 ]. However, in the majority of cases, isoforms from alternative splicing have not been well investigated.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Tao

2022

Biomolecules

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The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), play essential non-redundant roles in the regulation of energy homeostasis. Interaction of neural MCRs and melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) is suggested to play pivotal roles in MC3R and MC4R signaling. In the present study, we identified two new human (h) MRAP2 splice variants, MRAP2b (465 bp open reading frame) and MRAP2c (381 bp open reading frame). Human MRAP2s are different in C-termini. We investigated the effects of five isoforms of MRAPs, hMRAP1a, hMRAP1b, hMRAP2a, hMRAP2b, and hMRAP2c, on MC3R and MC4R pharmacology. At the hMC3R, hMRAP1a and hMRAP2c increased and hMRAP1b decreased the cell surface expression. hMRAP1a increased affinity to ACTH. Four MRAPs (hMRAP1a, hMRAP1b, hMRAP2a, and hMRAP2c) decreased the maximal responses in response to α-MSH and ACTH. For hMC4R, hMRAP1a, hMRAP2a, and hMRAP2c increased the cell surface expression of hMC4R. Human MRAP1b significantly increased affinity to ACTH while MRAP2a decreased affinity to ACTH. Human MRAP1a increased ACTH potency. MRAPs also affected hMC4R basal activities, with hMRAP1s increasing and hMRAP2s decreasing the basal activities. In summary, the newly identified splicing variants, hMRAP2b and hMRAP2c, could regulate MC3R and MC4R pharmacology. The two MRAP1s and three MRAP2s had differential effects on MC3R and MC4R trafficking, binding, and signaling. These findings led to a better understanding of the regulation of neural MCRs by MRAP1s and MRAP2s.

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Section: Discussionmentioning

confidence: 99%

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Tao

2022

Biomolecules

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“…Moreover, we found transcriptional deregulation of two other genes, Reep6 and Fabp7, which have been linked directly to retinal degeneration. It has been shown that Reep6 knockout mice display a rod degeneration phenotype [51]. In addition, several mutations have been identified in the REEP6 gene that are linked to the development of an autosomal recessive disease called Retinitis pigmentosa [52].…”

Section: Discussionmentioning

confidence: 99%

Identification of the Transcriptional Biomarkers Panel Linked to Pathological Remodelling of the Eye Tissues in Various HD Mouse Models

Mazur-Michałek

Ruciński

Sowiński

et al. 2022

Cells

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Ocular abnormalities are becoming associated with a spectrum of pathological events in various neurodegenerative diseases. Huntington’s disease (HD) is just such an example of a fatal neurological disorder, where mutated genes (CAG trinucleotide expansions in the Huntingtin gene) have widespread expression, leading to the production of mutant Huntingtin (mHTT) protein. It is well known that mutant HTT protein is prone to form toxic aggregates, which are a typical pathological feature, along with global transcriptome alterations. In this study, we employed well-established quantitative methods such as Affymetrix arrays and quantitative PCR (qPCR) to identify a set of transcriptional biomarkers that will track HD progression in three well-established mouse models: R6/2, R6/1, and HdhQ150. Our array analysis revealed significantly deregulated networks that are related to visual processes and muscle contractions. Furthermore, our targeted quantitative analysis identified a panel of biomarkers with some being dysregulated even at the presymptomatic stage of the disease, e.g., Opn1mw, Opn1sw, and Pfkfb2. Some of the deregulated genes identified in this study have been linked to other genetic ocular disorders such as: GNAT2, a source of achromatopsia, and REEP6, linked to Retinitis pigmentosa. It may thus be a useful platform for preclinical evaluations of therapeutic interventions.

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“…Alternative splicing is prevalent in eukaryotes and isoforms generated by alternative splicing might have different functions [ 82 , 83 , 84 , 85 ]. Splicing variants provide a nature-made chance to investigate the roles of specific domains.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2

Jiang

Tao

2022

Biomolecules

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The neural melanocortin receptors (MCRs), melanocortin-3 and -4 receptors (MC3R and MC4R), have crucial roles in regulating energy homeostasis. The melanocortin-2 receptor accessory proteins (MRAPs, MRAP1 and MRAP2) have been shown to regulate neural MCRs in a species-specific manner. The potential effects of MRAP1 and MRAP2 on canine neural MCRs have not been investigated before. Herein, we cloned canine (c) MC3R and identified one canine MRAP2 splice variant, MRAP2b, with N-terminal extension of cMRAP2a. Canine MC3R showed higher maximal responses to five agonists than those of human MC3R. We further investigated the modulation of cMRAP1, cMRAP2a, and cMRAP2b, on cMC3R and cMC4R pharmacology. For the cMC3R, all MRAPs had no effect on trafficking; cMRAP1 significantly decreased Bmax whereas cMRAP2a and cMRAP2b significantly increased Bmax. Both MRAP1 and MRAP2a decreased Rmaxs in response to α-MSH and ACTH; MRAP2b only decreased α-MSH-stimulated cAMP generation. For the MC4R, MRAP1 and MRAP2a increased cell surface expression, and MRAP1 and MRAP2a increased Bmaxs. All MRAPs had increased affinities to α-MSH and ACTH. MRAP2a increased ACTH-induced cAMP levels, whereas MRAP2b decreased α-MSH- and ACTH-stimulated cAMP production. These findings may lead to a better understanding of the regulation of neural MCRs by MRAP1 and MRAP2s.

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Transcript isoforms of Reep6 have distinct functions in the retina

Cited by 7 publications

References 38 publications

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Regulation of Melanocortin-3 and -4 Receptors by Isoforms of Melanocortin-2 Receptor Accessory Protein 1 and 2

Identification of the Transcriptional Biomarkers Panel Linked to Pathological Remodelling of the Eye Tissues in Various HD Mouse Models

Modulation of Canine Melanocortin-3 and -4 Receptors by Melanocortin-2 Receptor Accessory Protein 1 and 2

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