Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis

Guo, Dianlei; Ru, Jiali; Xie, Lijing; Wu, Mingjuan; Su, Yingchun; Zhu, Shi-Yong; Xu, Shujuan; Zou, Bin; Wei, Yanhong; Liu, Xialin; Liu, Yizhi; Liu, Chunqiao

doi:10.1073/pnas.2109934119

Cited by 13 publications

(8 citation statements)

References 57 publications

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“…In fact, photoreceptors light-sensing outer segments are specialized cilia, thus highly vulnerable in this setting. 24 Defective Rhodopsin trafficking is considered a common feature of RD in multiple ciliopathy models; moreover, in BBS animal models, endoplasmic reticulum stress response has been described. 25…”

Section: Retinal Dystrophymentioning

confidence: 99%

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Melluso¹,

Secondulfo²,

Capolongo³

et al. 2023

TCRM

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The Bardet Biedl syndrome (BBS) is a rare inherited disorder considered a model of non-motile ciliopathy. It is in fact caused by mutations of genes encoding for proteins mainly localized to the base of the cilium. Clinical features of BBS patients are widely shared with patients suffering from other ciliopathies, especially autosomal recessive syndromic disorders; moreover, mutations in cilia-related genes can cause different clinical ciliopathy entities. Besides the best-known clinical features, as retinal degeneration, learning disabilities, polydactyly, obesity and renal defects, several additional clinical signs have been reported in BBS, expanding our understanding of the complexity of its clinical spectrum. The present review aims to describe the current knowledge of BBS i) pathophysiology, ii) clinical manifestations, highlighting both the most common and the less described features, iii) current and future perspective for treatment.

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Section: Retinal Dystrophymentioning

confidence: 99%

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Melluso¹,

Secondulfo²,

Capolongo³

et al. 2023

TCRM

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“…E2F7 is essential to embryonic development and cell survival, and its dysfunction leads to apoptosis and dilation of blood vessels, resulting in embryonic death in mice (Li et al, 2008). TMEM138 is a connecting protein for cilium transport and biogenesis, and mice with mutated TMEM138 suffer from impaired primary cilia, learning and memory, resulting in Joubert syndrome (Guo et al, 2022). DNAH9 expressed on sperm tail is an important heavy chain component of the dynein arm of cilia and flagella, and mutation of DNAH9 leads to primary ciliary dyskinesia (PCD) and nonsyndromic asthenozoospermia (Fassad et al, 2018;Tang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics and transcriptional regulatory of spermatogenesis-related gene RFX2 in adult Banna mini-pig inbred line (BMI)

et al. 2023

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RFX2 plays critical roles in mammalian spermatogenesis and cilium maturation. Here, the testes of 12month-old adult boars of Banna mini-pig inbred line (BMI) were subjected to whole-transcriptome sequencing. The results indicated that the average expression (raw count) of RFX2 gene in BMI testes was 16138.25, and the average expression value of the corresponding transcript ENSSSCT00000043271.2 was 123.1898. The CDS of RFX2 obtained from BMI testes was 2,817 bp (GenBank accession number: OL362242). Gene structure analysis showed that RFX2 was located on chromosome 2 of the pig genome with 19 exons. Protein structure analysis indicated that RFX2 contains 728 amino acids with two conserved domains. Phylogenetic analysis revealed that RFX2 was highly conserved with evolutionary homologies among mammalian species. Other analyses, including PPI networks, KEGG, and GO, indicated that BMI RFX2 had interactions with 43 proteins involving various functions, such as in cell cycle, spermatid development, spermatid differentiation, cilium assembly, and cilium organization, etc. Correlation analysis between these proteins and the transcriptome data implied that RFX2 was significantly associated with FOXJ1, DNAH9, TMEM138, E2F7, and ATR, and particularly showed the highest correlation with ATR, demonstrating the importance of RFX2 and ART in spermatogenesis. Functional annotation implied that RFX2 was involved in 17 GO terms, including three cellular components (CC), six molecular functions (MF), and eight biological processes (BP). The analysis of miRNA-gene targeting indicated that BMI RFX2 was mainly regulated by two miRNAs, among which four lncRNAs and five lncRNAs competitively bound ssc-miR-365-5p and ssc-miR-744 with RFX2, respectively. Further, the dual-luciferase report assay indicated that the ssc-miR-365-5p and ssc-miR-744 significantly reduced luciferase activity of RFX2 3'UTR in the 293T cells, suggesting that these two miRNAs regulated the expression of RFX2. Our results revealed the important role of RFX2 in BMI spermatogenesis, making it an intriguing candidate for follow-up studies.

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“…After centrifugation, the supernatant was collected and prepared for Western blotting according to a standard protocol as previously described. 38 All primary antibodies for Western blotting (see the above antibody list for immunohistochemistry) were diluted at 1:1000–1: 2000 dilution. Secondary HRP‐conjugated antibodies, anti‐Rabbit IgG (ab6721, Abcam) and anti‐Rat IgG (ab97057, Abcam), were used at 1:5000 dilution.…”

Section: Methodsmentioning

confidence: 99%

“…For western blotting, proteins from both control and Prickle1 mutant EBs at D3 were extracted with RIPA buffer (R0278; Sigma‐Aldrich) with a protease inhibitor cocktail (P8340; Sigma‐Aldrich). After centrifugation, the supernatant was collected and prepared for Western blotting according to a standard protocol as previously described 38 . All primary antibodies for Western blotting (see the above antibody list for immunohistochemistry) were diluted at 1:1000–1: 2000 dilution.…”

Section: Methodsmentioning

confidence: 99%

Prickle1‐driven basement membrane deposition of the iPSC‐derived embryoid bodies is separable from the establishment of apicobasal polarity

Guo,

Liu,

Zhang

et al. 2024

Cell Proliferation

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Basement membrane (BM) component deposition is closely linked to the establishment of cell polarity. Previously, we showed that Prickle1 is crucial for BM deposition and cell polarity events in tear duct elongation. To gain a deeper understanding of the intimate relationship between BM formation and cell polarity, we generated induced pluripotent stem cells (iPSCs)‐derived embryoid bodies (EBs) with a basement membrane separating the visceral endoderm (VE) and inner EB cell mass. We found that Prickle1 was highly expressed in VE of the normal EBs, and the Prickle1 mutant EBs displayed severely impaired BM. Notably, the formation of the basement membrane appeared to rely on the proper microtubule network of the VE cells, which was disrupted in the Prickle1 mutant EBs. Moreover, disruption of vesicle trafficking in the VE hindered BM secretion. Furthermore, reintroducing Prickle1 in the mutant EBs completely rescued BM formation but not the apicobasal cell polarity of the VE. Our data, in conjunction with studies by others, highlight the conserved role of Prickle1 in directing the secretion of BM components of the VE cells during embryonic germ layer differentiation, even in the absence of established general polarity machinery. Our study introduces a novel system based on iPSCs‐derived EBs for investigating cellular and molecular events associated with cell polarity.

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Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis

Cited by 13 publications

References 57 publications

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Bardet-Biedl Syndrome: Current Perspectives and Clinical Outlook

Molecular characteristics and transcriptional regulatory of spermatogenesis-related gene RFX2 in adult Banna mini-pig inbred line (BMI)

Prickle1‐driven basement membrane deposition of the iPSC‐derived embryoid bodies is separable from the establishment of apicobasal polarity

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