Crystal structure of human PACRG in complex with MEIG1 reveals roles in axoneme formation and tubulin binding

Khan, Nimra; Pelletier, Dylan; McAlear, Thomas S; Croteau, Nathalie; Veyron, Simon; Bayne, Andrew N; Black, Corbin; Ichikawa, Muneyoshi; Khalifa, Ahmad Abdelzaher Zaki; Chaaban, Sami; Kurinov, Igor; Brouhard, Gary J.; Bechstedt, Susanne; Bui, Khanh Huy; Trempe, Jean‐François

doi:10.1016/j.str.2021.01.001

Cited by 20 publications

(23 citation statements)

References 67 publications

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“…1). The multiple contacts of CFAP20 with ciliary axoneme tubulins and PACRG, as well as proximity to CFAP52 and other proteins at or near the inner junction [19][20][21]71 (Figs. 1b and 8), could explain this degree of conservation.…”

Section: Discussionmentioning

confidence: 99%

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

et al. 2022

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Motile and non-motile cilia are associated with mutually-exclusive genetic disorders. Motile cilia propel sperm or extracellular fluids, and their dysfunction causes primary ciliary dyskinesia. Non-motile cilia serve as sensory/signalling antennae on most cell types, and their disruption causes single-organ ciliopathies such as retinopathies or multi-system syndromes. CFAP20 is a ciliopathy candidate known to modulate motile cilia in unicellular eukaryotes. We demonstrate that in zebrafish, cfap20 is required for motile cilia function, and in C. elegans, CFAP-20 maintains the structural integrity of non-motile cilia inner junctions, influencing sensory-dependent signalling and development. Human patients and zebrafish with CFAP20 mutations both exhibit retinal dystrophy. Hence, CFAP20 functions within a structural/functional hub centered on the inner junction that is shared between motile and non-motile cilia, and is distinct from other ciliopathy-associated domains or macromolecular complexes. Our findings suggest an uncharacterised pathomechanism for retinal dystrophy, and potentially for motile and non-motile ciliopathies in general.

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Section: Discussionmentioning

confidence: 99%

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

et al. 2022

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“…We also found high expression of Meig1 in ependymal cells (adjusted P = 1.08 × 10 −42 and 5.93 × 10 −86 in MNPQ and control samples, respectively). The Meig1 protein binds to the protein encoded by Pacrg , a gene co-regulated with Parkin (Khan et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…´ 10 -42 and 5.93 ´ 10 -86 in MNPQ and control samples, respectively). The Meig1 protein binds to the protein encoded by Pacrg, a gene co-regulated with Parkin (Khan et al, 2021).…”

Section: Gene Markers In Clustersmentioning

confidence: 99%

Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease

Ah¹,

Lee²,

Smith³

2022

Preprint

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Exposure to pesticides in humans increases the risk of Parkinson's disease (PD), but the mechanisms remain poorly understood. To elucidate these pathways, we dosed C57BL/6J mice with a combination of the pesticides maneb and paraquat (MNPQ). Behavioral analysis revealed motor deficits consistent with PD. Single cell RNA sequencing of substantia nigra pars compacta revealed both cell-type specific genes and genes expressed differentially between pesticide and control, including Fam241b, Emx2os, Bivm, Gm1439, Prdm15 and Rai2. Neurons had the largest number of significant differentially expressed genes, but comparable numbers were found in astrocytes and less so in oligodendrocytes. In addition, network analysis revealed enrichment in functions related to the extracellular matrix. These findings emphasize the importance of support cells in pesticide-induced PD and refocus our attention away from neurons as the sole agent of this disorder.

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“…Indeed, Meig1 and Tcfl5 appeared in our most correlated genes list. Both proteins, MEIG1 and SPAG16, have been described as important proteins for spermatids maturation and sperm motility [44][45][46][47] . The fact that TCFL5 interacts with proteins implicated in sperm flagellum formation suggests that TCFL5 could have another role besides as a transcription factor.…”

Section: Discussionmentioning

confidence: 99%

TCFL5 deficiency impairs the pachytene to diplotene transition during spermatogenesis in the mouse

Galán-Martínez

Berenguer

Maza

et al. 2022

Sci Rep

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Spermatogenesis is a complex, multistep process during which spermatogonia give rise to spermatozoa. Transcription Factor Like 5 (TCFL5) is a transcription factor that has been described expressed during spermatogenesis. In order to decipher the role of TCFL5 during in vivo spermatogenesis, we generated two mouse models. Ubiquitous removal of TCFL5 generated by breeding TCFL5fl/fl with SOX2-Cre mice resulted in sterile males being unable to produce spermatozoa due to a dramatic alteration of the testis architecture presenting meiosis arrest and lack of spermatids. SYCP3, SYCP1 and H1T expression analysis showed that TCFL5 deficiency causes alterations during pachytene/diplotene transition resulting in a meiotic arrest in a diplotene-like stage. Even more, TCFL5 deficient pachytene showed alterations in the number of MLH1 foci and the condensation of the sexual body. In addition, tamoxifen-inducible TCFL5 knockout mice showed, besides meiosis phenotype, alterations in the spermatids elongation process resulting in aberrant spermatids. Furthermore, TCFL5 deficiency increased spermatogonia maintenance genes (Dalz, Sox2, and Dmrt1) but also increased meiosis genes (Syce1, Stag3, and Morc2a) suggesting that the synaptonemal complex forms well, but cannot separate and meiosis does not proceed. TCFL5 is able to bind to the promoter of Syce1, Stag3, Dmrt1, and Syce1 suggesting a direct control of their expression. In conclusion, TCFL5 plays an essential role in spermatogenesis progression being indispensable for meiosis resolution and spermatids maturation.

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Crystal structure of human PACRG in complex with MEIG1 reveals roles in axoneme formation and tubulin binding

Cited by 20 publications

References 67 publications

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

The inner junction protein CFAP20 functions in motile and non-motile cilia and is critical for vision

Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease

TCFL5 deficiency impairs the pachytene to diplotene transition during spermatogenesis in the mouse

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