The Role of the LINC Complex in Sperm Development and Function

Abstract

The LINC (LInker of Nucleoskeleton and Cytoskeleton) complex is localized within the nuclear envelope and consists of SUN (Sad1/UNc84 homology domain-containing) proteins located in the inner nuclear membrane and KASH (Klarsicht/Anc1/Syne1 homology domain-containing) proteins located in the outer nuclear membrane, hence linking nuclear with cytoplasmic structures. While the nucleoplasm-facing side acts as a key player for correct pairing of homolog chromosomes and rapid chromosome movements during meiosis, the cytoplasm-facing side plays a pivotal role for sperm head development and proper acrosome formation during spermiogenesis. A further complex present in spermatozoa is involved in head-to-tail coupling. An intact LINC complex is crucial for the production of fertile sperm, as mutations in genes encoding for complex proteins are known to be associated with male subfertility in both mice and men. The present review provides a comprehensive overview on our current knowledge of LINC complex subtypes present in germ cells and its central role for male reproduction. Future studies on distinct LINC complex components are an absolute requirement to improve the diagnosis of idiopathic male factor infertility and the outcome of assisted reproduction.

Keywords: KASH; LINC complex; SUN; chromatin; cytoskeleton; male fertility; male germ cells; nucleoskeleton; sperm pathologies; spermatogenesis.

Figure 1

Schematic representation of LINC complex functions at different stages of sperm development. (A) Spermatocytes; heterotrimeric SUN1/2 forming a complex with KASH5 and enables chromosome movements during meiosis; KASH5 interacts with microtubules via dynein–dynactin (DD) complex. SUN1/2 is connected to TERB1, which recruits other nuclear proteins (TERB2, TRF1, and MAJIN) which have the capacity to bind to telomeric DNA repeats; TERB1 also binds to cohesin molecules thus stabilizing the connection between telomere and the LINC complex. (B) Spermatids (round and elongating—not shown) and mature spermatozoa; two distinct LINC complexes polarizes to the opposite poles of a sperm head; SUN1ŋ:KASH3 complex is associated with the acrosomal membrane at the anterior pole where it mediates the connection with the acroplaxome via plectin molecules; SUN3/4:KASH1, on the other hand, polarizes to the posterior pole of the sperm head and associates with the microtubule manchette in the cytoplasm.

Figure 2

Schematic representation of SUN3/4:KASH1 LINC complex and its connection to the nucleoskeleton and cytoskeleton. In cytoplasm, KASH1 tethers the microtubule manchette to NE thanks to its ability to bind to subunits of kinesin and dynein, that can move alongside the microtubules. The nucleoplasmic part of the LINC complex, SUN3/4, is connected to lamin B1 and also associates with SEPT12 (represented by the black broken line, PR—perinuclear ring).

Figure 3

Schematic representation of the HTCA arrangement and the SUN4 significance. (A) In wild type, the basal plate is tightly attached to the implantation fossa (IF) thanks to the SUN4 protein. (B) When SUN4 is missing, the lateral regions of the basal plate are clearly detached (indicated by black arrows) from the IF; the arrangement of HTCA remains intact under both circumstances.

Figure 4

Schematic representation of SUN5 function in mature spermatozoa. (A) SUN5 is localized to the very posterior pole of the sperm head where it connects it to the tail. (B) In the absence of SUN5, the sperm head detaches completely from the sperm tail; this results in release of decapitated sperm tails with only cytoplasmic droplets in the lumen of seminiferous tubules. This phenomenon is also called pseudo-globozoospermia.