Essential Roles of Efferent Duct Multicilia in Male Fertility

Abstract

Cilia are microtubule-based hair-like organelles on the cell surface. Cilia have been implicated in various biological processes ranging from mechanosensation to fluid movement. Ciliary dysfunction leads to a plethora of human diseases, known as ciliopathies. Although non-motile primary cilia are ubiquitous, motile multicilia are found in restricted locations of the body, such as the respiratory tract, the oviduct, the efferent duct, and the brain ventricles. Multicilia beat in a whip-like motion to generate fluid flow over the apical surface of an epithelium. The concerted ciliary motion provides the driving force critical for clearing airway mucus and debris, transporting ova from the ovary to the uterus, maintaining sperm in suspension, and circulating cerebrospinal fluid in the brain. In the male reproductive tract, multiciliated cells (MCCs) were first described in the mid-1800s, but their importance in male fertility remained elusive until recently. MCCs exist in the efferent ducts, which are small, highly convoluted tubules that connect the testis to the epididymis and play an essential role in male fertility. In this review, we will introduce multiciliogenesis, discuss mouse models of male infertility with defective multicilia, and summarize our current knowledge on the biological function of multicilia in the male reproductive tract.

Keywords: cilia; efferent ducts; fertility; multiciliated cells; spermatogenesis.

Figure 1

Multiciliated cell differentiation. Key factors and events for MCC differentiation are depicted. Repression of Notch signaling by miR-34/miR-449 triggers MCC differentiation. GEMC1 acts in a complex with E2F4/5 and DP1 to turn on MCIDAS and other ciliary genes necessary for centriole amplification, basal body docking, and cilium elongation. GMNN functions as an inhibitor of GEMC1 and MCIDAS. GMNN, geminin; GEMC1, geminin coiled-coil domain-containing protein 1; DEUP1, deuterosome assembly protein 1; CCNO, cyclin O; FOXJ1, forkhead box J1.

Figure 2

Model for localization (A) and function (B) of Cby1 and its associated proteins in airway MCCs. Cby1 clusters at the ciliary base as a ring with a diameter of 300 nm and a height of 100 nm [13]. Cby1 and its interactors are essential for the efficient docking of basal bodies to the apical membrane. TZ, transition zone; TF, transition fiber; DA, distal appendage; CV, ciliary vesicle.

Figure 3

Male reproductive tract. (A) Cartoon schematic of the male reproductive tract. Sperm are produced in the seminiferous tubules of the testis, collected in the rete testis, and transported to the epididymis via EDs, where they mature. Mature sperm are stored in the cauda epididymis and released through the vas deferens. (B) Depiction of a cross-section of the ED along the red dashed line in (A). The ED epithelium consists of MCCs and secretory cells.

Figure 4

Rete testis dilation and sperm aggregation in the EDs of the FOXJ1-Cre;Cep164^fl/fl mouse model. PAS staining of the rete testis (top) and H&E staining of EDs (bottom) from adult mice. Asterisks indicate the tubules of the rete testis. Scale bar, 200 μm. The boxed areas in yellow are magnified in the insets to show multicilia. Note the lack of multicilia in the EDs of FOXJ1-Cre;Cep164^fl/fl mice. Scale bars, 20 μm and 10 μm (magnified images).