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Showing DNAI4 — WDR78 is a alias.

DNAI4

Dynein axonemal intermediate chain 4 · UniProt Q5VTH9

Length
848 aa
Mass
94.6 kDa
Annotated
2026-06-09
23 papers in source corpus 6 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAI4 (also known as WDR78) is an axonemal inner dynein arm intermediate chain essential for the assembly and motility of motile cilia and sperm flagella (PMID:30060180, PMID:42083518). It is the vertebrate orthologue of Chlamydomonas IC138 and functions as a core component of the Dynein-f inner dynein arm complex, physically associating with the heavy chain DNAH2 and the IC140 orthologue WDR63 through a WD40-repeat-mediated interaction; depletion of DNAI4 prevents Dynein-f heavy and intermediate chains from localizing to the axoneme and paralyzes ciliary beat (PMID:30060180, PMID:34782613). Within the inner dynein arm it also binds TCTEX1D2 (PMID:39827215). In sperm, loss of DNAI4 produces oligoasthenoteratospermia with multiple morphological abnormalities of the flagellum—disorganized mitochondrial sheaths, outer dense fibers, and '9+2' axonemes missing both inner and outer dynein arms—accompanied by marked reduction of the inner dynein arm component DNAH10 (PMID:42083518). DNAI4 additionally interacts with the retrograde IFT-A component IFT144, and its loss downregulates other IFT-A subunits (IFT140, IFT122, IFT121) in sperm tails, linking it to intraflagellar transport (PMID:42083518). Loss-of-function causes male infertility in mice and ciliopathy phenotypes including hydrocephalus, randomized left-right asymmetry, and pronephric cysts in zebrafish (PMID:42083518, PMID:30060180).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 Low

    Before its ciliary role was known, WDR78/DNAI4 was identified as a regulated transcript, establishing that its pre-mRNA is subject to alternative splicing control.

    Evidence ZRANB2 overexpression in HeLa cells with exon array transcriptome analysis

    PMID:23666063

    Open questions at the time
    • Single transcriptomic screen with no validation specific to WDR78
    • No connection to ciliary or flagellar function established
    • Functional consequence of splice regulation unknown
  2. 2019 High

    Established DNAI4/WDR78 as the vertebrate IC138 orthologue and a Dynein-f inner dynein arm intermediate chain required for axonemal dynein localization and ciliary motility, answering what protein family it belongs to and what it does.

    Evidence Co-IP identifying Dnah2 and Wdr63 partners, RNAi in mouse ependymal cilia, and zebrafish morpholino knockdown with ciliary beat and localization readouts

    PMID:30060180

    Open questions at the time
    • Morpholino-based zebrafish phenotypes not confirmed by mutant
    • Mechanism by which it scaffolds Dynein-f heavy chains unresolved
    • Structural basis of complex assembly not defined
  3. 2021 Medium

    Mapped the DNAI4-WDR63 interaction to WD40-repeat domains and showed WDR63 requires DNAI4 for inner dynein arm assembly in sperm, defining the molecular interface for IDA construction.

    Evidence Co-IP domain mapping plus Wdr63 CRISPR knockout mouse TEM

    PMID:34782613

    Open questions at the time
    • DNAI4 role inferred via its WDR63 partner rather than direct DNAI4 manipulation
    • Single lab
    • Stoichiometry of the IDA subcomplex not determined
  4. 2025 Medium

    Identified TCTEX1D2 as an additional inner dynein arm binding partner of DNAI4, expanding the roster of IDA subunits it associates with during flagellum formation.

    Evidence Co-immunoprecipitation from mouse testes lysates (with concordant preprint from same lab)

    PMID:39827215 PMID:bio_10.1101_2024.06.27.600786

    Open questions at the time
    • Single Co-IP without reciprocal or orthogonal validation
    • Same lab for both reports
    • Functional consequence of the interaction not tested
  5. 2026 High

    Direct DNAI4 knockout established its requirement for sperm flagellum assembly and male fertility and linked it to retrograde IFT, resolving its in vivo physiological role and a transport connection.

    Evidence CRISPR/Cas9 Dnai4 knockout mice with EM, western blot (DNAH10 loss), and Co-IP with IFT144 plus IFT-A subunit loss

    PMID:42083518

    Open questions at the time
    • Whether the IFT144 interaction is direct versus complex-mediated not resolved
    • Human disease relevance not tested
    • How DNAI4 links IDA assembly to retrograde IFT mechanistically unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DNAI4 mechanistically coordinates inner dynein arm assembly with intraflagellar transport, and whether DNAI4 variants cause human ciliopathy or infertility, remain open.
  • No human patient mutation evidence in the corpus
  • No structural model of the DNAI4-containing IDA complex
  • Mechanism coupling IFT-A retrograde transport to dynein arm docking undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005929 cilium 2
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-1474165 Reproduction 1
Partners
DNAH10DNAH2IFT144TCTEX1D2WDR63
Complex memberships
axonemeinner dynein arm (Dynein-f)

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2026 DNAI4 (dynein axonemal intermediate chain 4) is required for sperm flagellum assembly and male fertility in mice; Dnai4 knockout causes oligoasthenoteratospermia with MMAF, including disorganized mitochondrial sheaths, outer dense fibers, '9+2' axonemes, and missing inner dynein arms (IDA) and outer dynein arms. The IDA component DNAH10 was markedly reduced in testes and sperm tails of knockout mice. CRISPR/Cas9 knockout mice, electron microscopy, western blot, RT-PCR Development (Cambridge, England) High 42083518
2026 DNAI4 physically interacts with the intraflagellar transport protein IFT144 (a retrograde IFT-A component) within mouse testes, and Dnai4 deletion leads to downregulation of other IFT-A members IFT140, IFT122, and IFT121 in sperm tails, placing DNAI4 upstream of retrograde intraflagellar transport. Co-immunoprecipitation from testes lysates; western blot of IFT subunits in Dnai4 KO sperm tails Development (Cambridge, England) Medium 42083518
2019 WDR78 (DNAI4) is the vertebrate orthologue of Chlamydomonas IC138 (an inner dynein arm intermediate chain). Wdr78 associates with Dynein-f subunits Dnah2 (a heavy chain) and Wdr63 (IC140 orthologue), and depletion of Wdr78 by RNAi causes all Dynein-f heavy chains and intermediate chains to fail to localize in mouse ependymal cilia, paralyzing ciliary beat. Zebrafish Wdr78 morphants display ciliopathy phenotypes (curved body, hydrocephalus, randomized left-right asymmetry, pronephric cysts) with paralyzed pronephric cilia. Co-immunoprecipitation, RNAi knockdown, high-speed video microscopy of cilia, zebrafish morpholino knockdown, immunofluorescence/localization Journal of molecular cell biology High 30060180
2021 WDR78 (DNAI4) interacts with WDR63 mainly via WD40-repeat domain interaction, and WDR63 requires WDR78 for proper inner dynein arm (IDA) assembly in sperm flagella. Loss of WDR63 causes absent inner dynein arms and disorganized '9+2' axonemes in spermatozoa. Co-immunoprecipitation (WDR63–WDR78 interaction), CRISPR-Cas9 Wdr63 knockout mice, transmission electron microscopy Cell discovery Medium 34782613
2025 WDR78 (DNAI4) interacts with TCTEX1D2 in mouse testes as a component of the inner dynein arm (axonemal dynein), establishing WDR78 as a binding partner of TCTEX1D2 within the inner dynein arm complex during sperm flagellum formation. Co-immunoprecipitation from mouse testes lysates Scientific reports Medium 39827215
2024 WDR78 (DNAI4) interacts with TCTEX1D2 in mouse testes as a component of the inner dynein arm, confirmed independently in a preprint from the same laboratory group. Co-immunoprecipitation from mouse testes lysates bioRxivpreprint Low bio_10.1101_2024.06.27.600786
2013 Overexpression of the splicing factor ZRANB2 in HeLa cells influences the alternative splicing of the WDR78 (DNAI4) primary transcript, indicating that WDR78 pre-mRNA is a regulated splicing target of ZRANB2. ZRANB2 overexpression in HeLa cells followed by Affymetrix Human Exon array transcriptome analysis Molecular biology reports Low 23666063

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Distinct specificities of inwardly rectifying K(+) channels for phosphoinositides. The Journal of biological chemistry 177 10593888
2008 Direct regulation of BK channels by phosphatidylinositol 4,5-bisphosphate as a novel signaling pathway. The Journal of general physiology 85 18562499
1975 Lipid specificity of beta-hydroxybutyrate dehydrogenase activation. The Journal of biological chemistry 73 1170169
2014 Structural basis of nSH2 regulation and lipid binding in PI3Kα. Oncotarget 66 25105564
2020 Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD. Gut 47 32651235
2021 Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly. Cell discovery 37 34782613
1990 Phenotypic characterization, karyotype analysis and in vitro tamoxifen sensitivity of new ER-negative vulvar carcinoma cell lines, UM-SCV-1A and UM-SCV-1B. International journal of cancer 37 2335395
2019 Vertebrate Dynein-f depends on Wdr78 for axonemal localization and is essential for ciliary beat. Journal of molecular cell biology 34 30060180
1991 Chromosomal abnormalities in giant cell tumors of bone. Cancer genetics and cytogenetics 32 1756493
2013 ZRANB2 localizes to supraspliceosomes and influences the alternative splicing of multiple genes in the transcriptome. Molecular biology reports 31 23666063
1996 dic(4;17)(p11;p11): a new recurrent chromosomal abnormality in chronic B-lymphoid disorders. Genes, chromosomes & cancer 18 8946198
1999 Endometrial stromal sarcoma with clonal complex chromosome abnormalities. Report of a case and review of the literature. Cancer genetics and cytogenetics 16 10432932
2020 Molecular insights into the development of hepatic metastases in colorectal cancer: a metastasis prediction study. European review for medical and pharmacological sciences 9 33378017
2014 1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D. Chemical biology & drug design 9 24641677
2024 Tanreqing suppresses the proliferation and migration of non-small cell lung cancer cells by mediating the inactivation of the HIF1α signaling pathway via exosomal circ-WDR78. Journal of biomolecular structure & dynamics 8 38247231
2023 Multiple Inositol Polyphosphate Phosphatase Compartmentalization Separates Inositol Phosphate Metabolism from Inositol Lipid Signaling. Biomolecules 7 37371464
2025 TCTEX1D2 is essential for sperm flagellum formation in mice. Scientific reports 5 39827215
2012 Establishment and characterization of a new human acute myelomonocytic leukemia cell line JIH-3. Leukemia research 3 22340903
2019 Tumorigenic effects of TLX overexpression in HEK 293T cells. Cancer reports (Hoboken, N.J.) 2 32721119
2016 Identifying New Drug Targets for Potent Phospholipase D Inhibitors: Combining Sequence Alignment, Molecular Docking, and Enzyme Activity/Binding Assays. Chemical biology & drug design 2 26691755
2023 Structural Insights Uncover the Specific Phosphoinositide Recognition by the PH1 Domain of Arap3. International journal of molecular sciences 1 36674645
2026 Comparative genomics reveals evolutionary signatures of genes associated with jumping in beetles. Zoological research 0 41566712
2026 DNAI4 is required for flagellum assembly and male fertility in mice. Development (Cambridge, England) 0 42083518

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