ZMYND10 functions in a chaperone relay during axonemal dynein assembly

Mali, Girish R.; Yeyati, Patricia L; Mizuno, Seiya; Keighren, Margaret; Lage, Petra zur; García-Muñoz, Amaya; Shimada, Atsuko; Takeda, Hiroyuki; Edlich, Frank; Takahashi, Satoru; Kriegsheim, Alex von; Jarman, Andrew P.; Mill, Pleasantine

doi:10.1101/233718

Cited by 7 publications

(7 citation statements)

References 45 publications

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“…Mutations in DNAAF1 are linked to tissue asymmetry development and primary ciliary dyskinesia (PCD) (Ferreira et al, 2018;Hartill et al, 2018). ZMYND10 is also required for the assembly of the dynein arms (Mali et al, 2018) and associated with PCD in humans (Moore et al, 2013). Loss of zmynd10 in medaka fish led to viable scoliosis, with vertebral malformations (Kobayashi et al, 2017), further supporting our results and analysis of scoliosis phenotypes using chimeric F0 mutagenesis approach in zebrafish.…”

Section: Discussionsupporting

confidence: 79%

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

Wang

Liu

Yang

et al. 2020

Front. Cell Dev. Biol.

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Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly understood. To identify additional AIS susceptibility loci, we performed whole-exome sequencing (WES) on a cohort of 195 Southern Chinese AIS patients. Bioinformatics analysis identified 237 novel rare variants associated with AIS, located in 232 new susceptibility loci. Enrichment analysis of these variants revealed 10 gene families associated with our AIS cohort. We screened these gene families by comparing our candidate gene list with IS candidate genes in the Human Phenotype Ontology (HPO) database and previous reported studies. Two candidate gene families, axonemal dynein and axonemal dynein assembly factors, were retained for their associations with ciliary architecture and function. The damaging effects of candidate variants in dynein genes dnali1, dnah1, dnaaf, and zmynd10, as well as in one fibrillin-related gene tns1, were functionally analyzed in zebrafish using targeted CRISPR/Cas9 screening. Knockout of two candidate genes, dnaaf1 or zmynd10, recapitulated scoliosis in viable adult zebrafish. Altogether, our results suggest that the disruption of one or more dynein-associated factors may correlate with AIS susceptibility in the Southern Chinese population.

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Section: Discussionsupporting

confidence: 79%

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

Wang

Liu

Yang

et al. 2020

Front. Cell Dev. Biol.

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“…In Drosophila, WDR92 has been recently linked to R2TP function during dynein assembly . Separately, the PCD protein ZMYND10 is involved in HC stabilization during which it recruits co-chaperone FKBP8 (Mali et al, 2018). Overall, the molecular evidence supports the notion that many DNAAFs function as cytoplasmic cochaperones.…”

Section: Introductionsupporting

confidence: 57%

The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

Lage

Lennon

et al. 2021

Biology Open

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Ciliary motility is powered by a suite of highly conserved axoneme-specific dynein motor complexes. In humans the impairment of these motors through mutation results in the disease, Primary Ciliary Dyskinesia (PCD). Studies in Drosophila have helped to validate several PCD genes whose products are required for cytoplasmic pre-assembly of axonemal dynein motors. Here we report the characterisation of the Drosophila orthologue of the less known assembly factor, DNAAF3. This gene, CG17669 (Dnaaf3), is expressed exclusively in developing mechanosensory chordotonal (Ch) neurons and the cells that generate spermatozoa, the only two Drosophila cell types bearing cilia/flagella containing dynein motors. Mutation of Dnaaf3 results in larvae that are deaf and adults that are uncoordinated, indicating defective Ch neuron function. The mutant Ch neuron cilia of the antenna specifically lack dynein arms, while Ca imaging in larvae reveals a complete loss of Ch neuron response to vibration stimulus, confirming that mechanotransduction relies on ciliary dynein motors. Mutant males are infertile with immotile sperm whose flagella lack dynein arms and show axoneme disruption. Analysis of proteomic changes suggest a reduction in heavy chains of all axonemal dynein forms, consistent with an impairment of dynein pre-assembly.

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“…An intriguing subset was enriched in cilia-related genes and uniquely expressed Sntn , a gene encoding for the apical ciliary protein Sentan (Kubo et al, 2008) (Figure 2C and 2D, Table S4). Sntn is a known marker of mature ciliated cells in the airways and oviducts (He et al, 2020; Konishi et al, 2016; Kubo et al, 2008; Mali et al, 2018), which suggests that it marks mature ependymal cells. Other molecular features of Sntn cells such as higher expression of the cyclin-dependent kinase inhibitor p21 gene ( Cdkn1a ) and histone genes ( Hist1h1c , Hist1h4h and Hist1h4i ), suggest ongoing change in the cell cycle state and chromatin organisation of these cells.…”

Section: Resultsmentioning

confidence: 99%

Ependymal cell maturation is heterogeneous and ongoing in the mouse spinal cord and dynamically regulated in response to injury

Albors

Singer

May

et al. 2022

Preprint

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SummaryThe spinal cord neural stem cell potential resides within the ependymal cells lining the central canal. These cells are, however, heterogeneous, and we know little about the biological diversity this represents. Here we use single-cell RNA-sequencing to profile adult mouse spinal cord ependymal cells. We uncover transcriptomes of known subtypes and a new mature ependymal cell state, that becomes more prominent with age. Comparison of ependymal cell transcriptomes from the brain and spinal cord revealed that ongoing cell maturation distinguishes spinal cord ependymal cells from their postmitotic brain counterparts. Using an ex vivo model of spinal cord injury, we show that ependymal cell maturation is reversible but also highly regulated. We revisit ependymal cell identities in adult human spinal cord and uncover evidence for their maturation and surprising ventralisation with age. This first in-depth characterisation of spinal cord ependymal cells paves the way to manipulation of distinct ependymal subtypes, provides insights into ependymal cell maturation dynamics and informs strategies for coaxing ependymal cell-driven spinal cord repair.

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ZMYND10 functions in a chaperone relay during axonemal dynein assembly

Cited by 7 publications

References 45 publications

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes

The Drosophila orthologue of the primary ciliary dyskinesia-associated gene, DNAAF3, is required for axonemal dynein assembly

Ependymal cell maturation is heterogeneous and ongoing in the mouse spinal cord and dynamically regulated in response to injury

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