Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation

Abstract

The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically relevant roles beyond β-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post-transcriptional sperm maturation program and invite revisiting transcription-independent Wnt signaling in somatic cells as well.

Radial Spokes—A Snapshot of the Motility Regulation, Assembly, and Evolution of Cilia and Flagella

“…Consistent with this, the calciumdependent waveform changes appeared missing in 9þ0 sperm flagella (Gibbons et al 1985). Contrary to the expected universal principle of mechanical feedback, the mechanisms of chemical signaling may differ substantially for Chlamydomonas, which use two relatively short flagella to steer, and for sperm's long flagella, which are activated by Wnt signaling (Koch et al 2015).…”

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

“…However, emerging data suggest that "canonical" Wnt signaling (Wnt signaling that depends on the Axin-APC-GSK-3 complex) regulates multiple processes that are independent of ␤-catenin and the transcriptional response to ␤-catenin/Tcf activation, including mitotic spindle orientation (71), mTORC1 activity (15,72,73), and protein stability (18,23,51,52,74). For example, Wnt-dependent stabilization of proteins (Wnt/STOP), which occurs primarily at the onset of mitosis, leads to stabilization of multiple proteins in addition to ␤-catenin, consistent with a role for GSK-3 in the canonical pathway that bypasses ␤-catenin/TCF transcription (51) (23,51,52,75,76). However, the overlap between the set of GSK-3-dependent phosphopeptides and the group of proteins that either increased (12 proteins) or decreased (4 proteins) in abundance was limited.…”

Segment-specific regulation of epididymal gene expression

“…Thus, although being composed of a single convoluted tubule, the structural organization of the epididymis allows local paracrine signaling to occur in a segment-specific manner. and Wnt (Koch et al 2015). CAP, caput; CAU, cauda; COR, corpus; IS, initial segment.…”

“…Many genes exhibit cell type and segment-specific expression patterns, where expression can be restricted to one particular subsegment. Additionally, several gene families, for example, prostate and testis expression (Pate, Turunen et al 2011) and wingless-type MMTV integration site family (Wnt, Koch et al 2015), display distinct expression patterns along the tissue; certain family members are restricted to specific epididymal regions, whereas other members are present in the whole tissue (Fig. 2).…”

“…In addition, epididymal membrane vesicles, epididymosomes, have been shown to transfer proteins and lipids to the spermatozoa, thus changing, for example, the sperm lipid content during epididymal maturation (Saez et al 2011, Sullivan & Saez 2013. Interesting new results reveal how epididymal Wnt signaling controls sperm maturation via epididymosomes by affecting target protein phosphorylation and global protein ubiquitination in sperm (Koch et al 2015). Furthermore, it seems plausible that the epididymis transfers the information about epigenetic changes caused by environmental factors, such as paternal diet, to sperm via epididymosomal transport of tRNA fragments (Sharma et al 2016).…”