The heat shock protein family gene<i>Hspa1l</i>in male mice is dispensable for fertility

Wang, Xin; Xie, Wenxiu; Yao, Yejin; Zhu, Yunfei; Zhou, Jianli; Cui, Yiqiang; Guo, Xuejiang; Yan, Yuan; Zhou, Zuomin; Liu, Mingxi

doi:10.7717/peerj.8702

Cited by 15 publications

(15 citation statements)

References 46 publications

(63 reference statements)

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“…In the present study, both of the two variants in WDR63 are located before the WD40 domain (p.Arg55* and p.Arg359*), leading to the loss of WD40 domains in WDR63 protein. The basic common function of all WD40-repeat proteins is to coordinate the assembly of multi-protein complex, where the repeating units act as a rigid scaffolds for protein interactions 22 . The complex structure of sperm flagella contained a series of WD40-domain-containing proteins 1 , 23 .…”

Section: Discussionmentioning

confidence: 99%

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

Lü

et al. 2021

Cell Discov

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Inner dynein arm (IDA), composed of a series of protein complex, is necessary to cilia and flagella bend formation and beating. Previous studies indicated that defects of IDA protein complex result in multiple morphological abnormalities of the sperm flagellum (MMAF) and male infertility. However, the genetic causes and molecular mechanisms in the IDAs need further exploration. Here we identified two loss-of-function variants of WDR63 in both MMAF and non-obstructive azoospermia (NOA) affected cohorts. WDR63 encodes an IDA-associated protein that is dominantly expressed in testis. We next generated Wdr63-knockout (Wdr63-KO) mice through the CRISPR-Cas9 technology. Remarkably, Wdr63-KO induced decreased sperm number, abnormal flagellar morphology and male infertility. In addition, transmission electron microscopy assay showed severely disorganized “9 + 2” axoneme and absent inner dynein arms in the spermatozoa from Wdr63-KO male mice. Mechanistically, we found that WDR63 interacted with WDR78 mainly via WD40-repeat domain and is necessary for IDA assembly. Furthermore, WDR63-associated male infertility in human and mice could be overcome by intracytoplasmic sperm injection (ICSI) treatment. In conclusion, the present study demonstrates that bi-allelic variants of WDR63 cause male infertility via abnormal inner dynein arms assembly and flagella formation and can be used as a genetic diagnostic indicator for infertility males.

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Section: Discussionmentioning

confidence: 99%

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

Lü

et al. 2021

Cell Discov

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“…Previous report demonstrated that HSPA1L is mainly expressed in testis, and located in cytosol or nucleus 18 . Recently, Wang et al reported mRNA expressions of Hspa1l in mouse heart, liver, spleen, ling, kidney, brain, muscle, and testis 28 . We also detected the gene expression of Hspa1l in C57BL/6J mouse kidney tissues (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

et al. 2021

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Proximal tubular cells (PTCs) are crucial for maintaining renal homeostasis, and tubular injuries contribute to progression of diabetic kidney disease (DKD). However, the roles of visceral adipose tissue-derived serine protease inhibitor (vaspin) in the development of DKD is not known. We found vaspin maintains PTCs through ameliorating ER stress, autophagy impairment, and lysosome dysfunction in DKD. Vaspin−/− obese mice showed enlarged and leaky lysosomes in PTCs associated with increased apoptosis, and these abnormalities were also observed in the patients with DKD. During internalization into PTCs, vaspin formed a complex with heat shock protein family A (Hsp70) member 1 like (HSPA1L) as well as 78 kDa glucose-regulated protein (GRP78). Both vaspin-partners bind to clathrin heavy chain and involve in the endocytosis. Notably, albumin-overload enhanced extracellular release of HSPA1L and overexpression of HSPA1L dissolved organelle stresses, especially autophagy impairment. Thus, vapsin/HSPA1L-mediated pathways play critical roles in maintaining organellar function of PTCs in DKD.

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“…In the binding of sperm to the zona pellucida GO term, we found several genes associated with spermatogenesis and fertilization, namely, HSPA1L (heat shock protein family A member 1 like), SPA17 (sperm autoantigenic protein 17), ZPBP (zona pellucida binding protein), and ZPBP2 (zona pellucida binding protein 2). HSPA1L has also been shown to be related to spermiogenesis in cattle, human, and mouse (Liu et al, 2019;Wang et al, 2020). This implies that DNA methylation patterns of key genes associated with spermatogenesis are highly conserved across species (Figure 3D, Supplementary Table S2).…”

Section: General Characteristics Of Sperm Dna Methylomementioning

confidence: 91%

Comparative Analyses of Sperm DNA Methylomes Among Three Commercial Pig Breeds Reveal Vital Hypomethylated Regions Associated With Spermatogenesis and Embryonic Development

Chen

Liu

et al. 2021

Front. Genet.

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Identifying epigenetic changes is essential for an in-depth understanding of phenotypic diversity and pigs as the human medical model for anatomizing complex diseases. Abnormal sperm DNA methylation can lead to male infertility, fetal development failure, and affect the phenotypic traits of offspring. However, the whole genome epigenome map in pig sperm is lacking to date. In this study, we profiled methylation levels of cytosine in three commercial pig breeds, Landrace, Duroc, and Large White using whole-genome bisulfite sequencing (WGBS). The results showed that the correlation of methylation levels between Landrace and Large White pigs was higher. We found that 1,040–1,666 breed-specific hypomethylated regions (HMRs) were associated with embryonic developmental and economically complex traits for each breed. By integrating reduced representation bisulfite sequencing (RRBS) public data of pig testis, 1743 conservated HMRs between sperm and testis were defined, which may play a role in spermatogenesis. In addition, we found that the DNA methylation patterns of human and pig sperm showed high similarity by integrating public data from WGBS and chromatin immunoprecipitation sequencing (ChIP-seq) in other mammals, such as human and mouse. We identified 2,733 conserved HMRs between human and pig involved in organ development and brain-related traits, such as NLGN1 (neuroligin 1) containing a conserved-HMR between human and pig. Our results revealed the similarities and diversity of sperm methylation patterns among three commercial pig breeds and between human and pig. These findings are beneficial for elucidating the mechanism of male fertility, and the changes in commercial traits that undergo strong selection.

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The heat shock protein family geneHspa1lin male mice is dispensable for fertility

Cited by 15 publications

References 46 publications

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

Bi-allelic variants in human WDR63 cause male infertility via abnormal inner dynein arms assembly

A Vaspin–HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease

Comparative Analyses of Sperm DNA Methylomes Among Three Commercial Pig Breeds Reveal Vital Hypomethylated Regions Associated With Spermatogenesis and Embryonic Development

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