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Mettl3 regulates lens development by promoting the differentiation processes of secondary fiber cells [RNA-seq]

ABSTRACT: Lens development requires tight regulation of cell proliferation and differentiation processes, the disruption of which leads to congenital cataract formation. N6-methyladenosine (m6A) is the most prevalent internal mRNA internal modification and has been shown to play important roles in regulating the development, physiology and pathology of various organs and tissues. However, the function of m6A during lens development remains unknown. In this study, we used lens-specific Mettl3 conditional knockout mice as a model to study the function of Mettl3 during lens development. Our study revealed that Mettl3 plays essential role in lens development by promoting the differentiation processes of secondary fiber cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE287640 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Mutations of the RNA-granule component TDRD7 (OMIM: 611258) cause pediatric cataract in humans. Here, we applied an integrated approach to elucidate the molecular pathology of cataract in Tdrd7 targeted-knockout (Tdrd7-/-) mice. Tdrd7-/- animals precipitously develop lens fiber cell abnormalities early in life, suggesting a global-level breakdown/mis-regulation of key cellular processes. High-throughput RNA-sequencing followed by iSyTE-integrated bioinformatics-based analysis identified the molecular chaperone and cytoskeletal-modulator, HSPB1 (HSP27), among the high-priority down-regulated candidates in Tdrd7-/- lens. Moreover, a protein 2-D fluorescence difference gel electrophoresis-coupled mass spectrometry screen also identified HSPB1 to be reduced in Tdrd7-/- lens, offering independent support for focusing efforts on this factor to explain Tdrd7-/- cataract. Reduction of HSPB1 preceded lens morphological abnormalities, suggesting that cytoskeletal defects underlie the Tdrd7-/- cataract phenotype. In agreement, scanning electron microscopy revealed abnormal fiber cell membrane protrusions in Tdrd7-/- lenses. Significantly, abnormal F-actin staining was detected specifically in Tdrd7-/- fiber cells that exhibit nuclear degradation, thereby revealing that there are distinct mechanisms based on pre- or post-nuclear degradation differentiation stage for F-actin cytoskeletal maintenance in fiber cells. Further, RNA-immunoprecipitation identified Hspb1 mRNA in wild-type lens lysate TDRD7-pulldowns, and single-molecule RNA-imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in a specific pre-nuclear degradation area of differentiating fiber cells, indicating that TDRD7-ribonucleoprotein complexes are necessary for controlling optimal levels of key factors in lens development. Together, these data uncover a novel role for TDRD7 in regulating elevation of stress-responsive chaperones for cytoskeletal maintenance in post-nuclear degradation lens fiber cells, perturbation of which causes early-onset cataracts.

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Mettl3 regulates lens development by promoting the differentiation processes of secondary fiber cells [RNA-seq]

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