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TDRD7 participates in lens development and spermiogenesis by mediating autophagosome maturation
Chaofeng Tu1,2,3, Haiyu Li1, Xuyang Liu4
1Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.
Abstract:
In humans, TDRD7 (tudor domain containing 7) mutations lead to a syndrome combining congenital cataracts (CCs) and non-obstructive azoospermia (NOA), characterized by abnormal lens development and spermiogenesis. However, the molecular mechanism underlying TDRD7's functions in eye and testicular development are still largely unknown. Here, we show that the depletion of this gene in mice and humans resulted in the accumulation of autophagosomes and the disruption of macroautophagic/autophagic flux. The disrupted autophagic flux in tdrd7-deficient mouse embryonic fibroblasts (MEFs) was caused by a failure of autophagosome fusion with lysosomes. Furthermore, transcriptome analysis and biochemical assays showed that TDRD7 might directly bind to Tbc1d20 mRNAs and downregulate its expression, which is a key regulator of autophagosome maturation, resulting in the disruption of autophagosome maturation. In addition, we provide evidence to show that TDRD7-mediated autophagosome maturation maintains lens transparency by facilitating the removal of damaged proteins and organelles from lens fiber cells and the biogenesis of acrosome. Altogether, our results showed that TDRD7 plays an essential role in the maturation of autophagosomes and that tdrd7 deletion results in eye defects and testicular abnormalities in mice, implicating disrupted autophagy might be the mechanism that contributes to lens development and spermiogenesis defects in human.Abbreviations: CB: chromatoid bodies; CC: congenital cataract; CTSD: cathepsin D; DMSO: dimethyl sulfoxide; LAMP1: lysosomal-associated membrane protein 1; LECs: lens epithelial cells; MAP1LC3/LC3/Atg8: microtubule-associated protein 1 light chain 3; MEFs: mouse embryonic fibroblasts; NOA: non-obstructive azoospermia; OFZ: organelle-free zone; RG: RNA granules; SQSTM1/p62: sequestosome 1; TBC1D20: TBC1 domain family member 20; TDRD7: tudor domain containing 7; TEM: transmission electron microscopy; WT: wild type.
Insights
Tudor domain containing 7 (TDRD7) is crucial for autophagosome maturation, essential for eye and testicular development. Its depletion causes cataracts and infertility by disrupting autophagy.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Mutations in TDRD7 (tudor domain containing 7) cause a human syndrome with congenital cataracts (CCs) and non-obstructive azoospermia (NOA).
- The precise molecular mechanisms of TDRD7 in ocular and testicular development remain largely unelucidated.
Purpose of the Study:
- To investigate the molecular function of TDRD7 in autophagy.
- To elucidate the role of TDRD7 in lens and sperm development.
Main Methods:
- Depletion of TDRD7 in mouse embryonic fibroblasts (MEFs) and analysis of autophagic flux.
- Transcriptome analysis and biochemical assays to identify TDRD7 interacting partners and targets.
- Assessment of lens and testicular phenotypes in TDRD7-deficient mice.
Main Results:
- TDRD7 depletion leads to autophagosome accumulation and impaired autophagic flux due to failed autophagosome-lysosome fusion.
- TDRD7 directly binds to TBC1D20 mRNA, downregulating its expression and disrupting autophagosome maturation.
- TDRD7 deficiency in mice causes congenital cataracts and defects in spermiogenesis, mirroring human disease phenotypes.
Conclusions:
- TDRD7 is essential for autophagosome maturation, regulating lens transparency and sperm development.
- Disrupted autophagy due to TDRD7 dysfunction is implicated as a key mechanism underlying congenital cataracts and non-obstructive azoospermia.
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