12/13/2023 0 Comments Ne x the talos principle imagesThe discovery of axonemal dyneins provides some insight into the mysterious mechanism of flagellar bending motion. Distal to MS, FS is a tapered cylinder that consists of two longitudinal columns (LCs) with nearly symmetrical distribution, and several connecting circumferential ribs (CRs) distributed between the LCs. ODFs are surrounded by the spiral MS in the middle region and by FS in the principal region. Based on these discrete subcellular structures along the longitudinal axis, the flagellum can be classified into three segments, namely, the middle, principal, and end pieces. In addition, several accessory subunits, comprising the nine outer dense fibers (ODFs), mitochondrial sheath (MS), and fibrous sheath (FS), layer by layer encompass different segments of the central axoneme. Mechanical links formed by radial spokes, dynein arms, and nexin-dynein regulatory complex (N-DRC) maintain the integrity and coordinate the dynamics of these microtubules. The axoneme is permanently located in the center of the flagellum and consists of nine peripheral doublet microtubules (DMTs), which circumferentially surround a central microtubular pair (CP) to form the classical ‘9 + 2’ arrangements. This highly conserved and microtubular organelle is precisely organized by a core cytoskeletal structure known as the axoneme, as well as a variety of peri-axonemal elements. Sperm flagellum is uniquely designed for its key biological role of beating wave formation. Asthenozoospermia (ASZ) is a frequent form of primary male infertility, whereby over 40% of cases present some defects in sperm motility. Sperm motility is critical for male fertility since the ejaculated sperm must self-propel its travel along the long female reproductive system to fertilize the egg and initiate life. Collectively, we demonstrate that DNALI1 is a newly causative gene for AZS in both humans and mice, which possesses multiple crucial roles in modulating flagellar assembly and motility. Finally, intracytoplasmic sperm injection (ICSI) can effectively resolve patient infertility. We conclude that a DNALI deficiency-induced IDAs injury and an asymmetric FS-driven tail rigid structure alteration may simultaneously cause flagellum immotility. Hence, DNALI1 may possess a non-classical molecular function, whereby it regulates the cytoplasmic dynein complex that assembles the flagella. Furthermore, DNALI1 loss severely disrupted the transport and assembly of the FS proteins, especially AKAP3 and AKAP4, during flagellogenesis. Immunoprecipitation revealed that DNALI1 might interact with the cytoplasmic dynein complex proteins in the testes. More importantly, we revealed that DNALI1 loss contributed to asymmetries in the most fibrous sheath (FS) of the sperm flagellum in both species. We identified loss of sperm DNAH1 and DNAH7 rather than DNAH10 in both DNALI1 663_666del patient and Dnali1 −/− mice, demonstrating that mammalian DNALI1 is a LIC protein of a partial IDA subspecies. Herein, we detected bi-allelic DNALI1 mutations, in an ASZ patient, which resulted in the complete loss of the DNALI1 in the patient’s sperm. Till now, a variety of dynein protein deficiencies have been linked with asthenospermia (ASZ), highlighting the significance of these structures in human sperm motility. They hydrolyze ATP to promote ciliary and flagellar movement. The axonemal dynein arms (outer (ODA) and inner dynein arms (IDAs)) are multiprotein structures organized by light, intermediate, light intermediate (LIC), and heavy chain proteins.
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