Disrupted intercellular bridges and spermatogenesis in fatty acyl‐CoA reductase 1 knockout mice: A new model of ether lipid deficiency. Issue 5 (11th April 2023)

• Record Type: Journal Article
• Authors: Pan, Bo; Yuan, Shuo; Mayernik, Linda; Yap, Yi Tian; Moin, Kamiar; Chung, Charles S.; Maddipati, Krishnarao; Krawetz, Stephen A.; Zhang, Zhibing; Hess, Rex A.; Chen, Xuequn
• Is Part Of: FASEB journal. Volume 37:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-04-11
• Subjects: ether lipids -- fatty acyl‐CoA reductase 1 -- intercellular bridge -- RNA sequencing -- spermatogenesis; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.202201848R
• Languages: English
• ISSNs: 0892-6638

Abstract

Abstract: Peroxisomal fatty acyl‐CoA reductase 1 (FAR1) is a rate‐limiting enzyme for ether lipid (EL) synthesis. Gene mutations in FAR1 cause a rare human disease. Furthermore, altered EL homeostasis has also been associated with various prevalent human diseases. Despite their importance in human health, the exact cellular functions of FAR1 and EL are not well‐understood. Here, we report the generation and initial characterization of the first Far1 knockout (KO) mouse model. Far1 KO mice were subviable and displayed growth retardation. The adult KO male mice had smaller testes and were infertile. H&E and immunofluorescent staining showed fewer germ cells in seminiferous tubules. Round spermatids were present but no elongated spermatids or spermatozoa were observed, suggesting a spermatogenesis arrest at this stage. Large multi‐nucleated giant cells (MGC) were found lining the lumen of seminiferous tubules with many of them undergoing apoptosis. The immunofluorescent signal of TEX14, an essential component of intercellular bridges (ICB) between developing germ cells, was greatly reduced and mislocalized in KO testis, suggesting the disrupted ICBs as an underlying cause of MGC formation. Integrative analysis of our total testis RNA‐sequencing results and published single‐cell RNA‐sequencing data unveiled cell type‐specific molecular alterations underlying the spermatogenesis arrest. Many genes essential for late germ cell development showed dramatic downregulation, whereas genes essential for extracellular matrix dynamics and cell–cell interactions were among the most upregulated genes. Together, this work identified the cell type‐specific requirement of ELs in spermatogenesis and suggested a critical role of Far1/ELs in the formation/maintenance of ICB during meiosis. Abstract : In this study, we reported the generation and initial characterization of the first Far1 knockout mouse model. The adult KO male mice were infertile with a spermatogenesis arrest at the round spermatid stage. Large multi‐nucleated giant cells (MGC) were in the lumen of seminiferous tubules. Our results suggest a critical role for Far1 and ELs in intercellular bridge (ICB) formation/stabilization and the disrupted ICB as one of the reasons for the massive germ cell loss in EL deficiency.