Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation

• Published in: Cell Vol. 163; no. 5; pp. 1225 - 1236
• Main Authors: Koch, Stefan, Acebron, Sergio P., Herbst, Jessica, Hatiboglu, Gencay, Niehrs, Christof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.11.2015
• Subjects: Animals; Axin Protein - metabolism; Cyclins - metabolism; Epididymis - metabolism; Gene Expression Regulation; Glycogen Synthase Kinase 3 - metabolism; Male; Mice; Phosphorylation; Post-Transcriptional; Post-Translational; Protein Processing; Protein Processing, Post-Translational; RNA Processing; RNA Processing, Post-Transcriptional; Septins - metabolism; Sperm Maturation; Wnt Signaling Pathway
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2015.10.029

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. [Display omitted] •Mammalian spermatozoa are Wnt-responsive cells•Wnt signaling controls sperm maturation independent of β-catenin•Wnt ligands promote sperm proteome stability (Wnt/STOP) and sperm motility•GSK3 is a septin 4 kinase that inhibits septin clustering Although the impact of canonical Wnt signaling is predominantly thought to necessitate β-catenin-dependent transcription, a multifaceted set of Wnt functions in sperm development is implemented post-transcriptionally through mechanisms that maybe relevant to other tissues as well.