Lumicrine signaling: Extracellular regulation of sperm maturation in the male reproductive tract lumen

Abstract

The behaviors of cells, tissues, and organs are controlled by the extracellular environment in addition to their autonomous regulatory system. Dysfunction of extracellular regulatory mechanisms affects not only the development and survival of organisms but also successful reproduction. In this review article, a novel extracellular regulatory mechanism regulating the mammalian male reproductive ability will be briefly summarized. In terrestrial vertebrates, spermatozoa generated in the testis are transported through the lumen of the male reproductive tract and become functionally mature during the transport. Recent studies with gene-modified animals are unveiling the luminal extracellular environment of the reproductive tract to function not only as the pathway of sperm transport and the site of sperm maturation but also as the channel for cellular communication to regulate sperm maturation. Of special interest is the molecular mechanism of lumicrine signaling, a transluminal secreted signal transduction in the male reproductive tract lumen as a master regulator of sperm maturation and male reproductive ability. The general significance of such transluminal signaling in the context of cell biology will also be discussed.

Keywords: Lumicrine; NELL2; epididymis; signal transduction; sperm maturation.

FIGURE 1

The epididymis is the site where sperm maturation occurs. (a) A schematic representation of male reproductive organs. Spermatozoa are generated inside seminiferous tubules of the testis, whereas they become mature in the epididymis. The lumens of the testicular seminiferous tubules and the epididymis are connected by the efferent duct. (b) Histology of the wild‐type (upper) and Nell2 KO (lower) epididymal initial segments. Scale bar, 50 μm. (c) A schematic representation of lumicrine component proteins NELL2, NICOL, and ROS1. (d) A schematic representation of NELL2, NICOL, and ROS1 molecular functions. KO, knockout.

FIGURE 2

Lumicrine regulation of sperm maturation. (a) A schematic representation of sperm maturation in the epididymal lumen. Epididymal epithelium secretes various proteins in response to the testicular lumicrine signal. Spermatozoa become mature under the influence of such proteins, but the detailed mechanisms are uncertain. (b) Downregulation of lumicrine‐regulated expression of OVCH2, ADAM28, and RNASE10 in the epididymal initial segment of wild‐type (WT) and Nell2 KO mice. GPX5 is also shown as an internal control. Note the almost complete loss of OVCH2, RNASE10, and ADAM28 expression in the lumicrine‐deficient Nell2 KO initial segment epididymis. (c) Proteins secreted from the epididymis under the control of lumicrine signaling and their known functions. KO, knockout.

FIGURE 3

Comparison of lumicrine signaling to growth factor/morphogen‐mediated signaling. (a) A schematic representation of conventional ECM and growth factor/morphogen‐mediated signaling, which occurs on the basolateral surface of epithelial cells. (b) A schematic representation of lumicrine signaling in the epididymis. Lumicrine signaling occurs on the apical surface. ECM, extracellular matrix.