Editors' ChoiceReproductive Biology

Every sperm needs Wnt

Sci. Signal.  01 Dec 2015:
Vol. 8, Issue 405, pp. ec356
DOI: 10.1126/scisignal.aad9456

Activation of the Wnt signaling pathway suppresses the GSK3-mediated phosphorylation of the transcription factor β-catenin and other proteins, which attenuates the proteasomal degradation of these proteins. Whereas stabilization of β-catenin results in the transcriptional activation of target genes, stabilization of other GSK3 targets can trigger nontranscriptional signaling events, which Koch et al. (see also De Robertis and Plope) investigated in sperm, which are not transcriptionally active cells. Cyclin Y–like 1 (Ccnyl1) promotes the phosphorylation, and thus activation, of the Wnt receptor LRP6 in germ cells in the testis, and the sperm of Ccnyl1–/– mice had structural and motility defects and impaired ability to fertilize oocytes in vitro. The structural defects arose during transit through the epididymis, suggesting that sperm maturation in Ccnyl1–/– mice was compromised. Epididymal luminal fluid in wild-type mice contained exosomes bearing Wnt2b, which triggered the activating phosphorylation of LRP6 when applied to sperm collected from all sections of the epididymis of wild-type mice, a response that was reduced in sperm from Ccnyl1–/– mice. Ubiquitylation of various GSK3 targets was increased in sperm collected from the cauda (terminal portion of the epididymis) of Ccnyl1–/– mice compared with that from wild-type mice, leading the authors to evaluate specific GSK3 targets involved in morphology and motility. In transfected HEK cells, GSK3β phosphorylated Septin 4, a GTPase that is required for the formation of a diffusion barrier that ensures proper localization of membrane proteins in sperm. Septin 4 from Ccnyl1–/– sperm did not form higher molecular weight structures in vitro, and the membrane protein basigin did not show restricted localization in Ccnyl1–/– sperm. By dephosphorylating various proteins involved in sperm motility, PP1 activity keeps sperm in an immotile state, and GSK3 promotes PP1 activity by phosphorylating PPP1R2, an inhibitory subunit of PP1. PPP1R2 phosphorylation and PP1 activity were increased in Ccnyl1–/– sperm, and the motility of sperm from wild-type or Ccnyl1 heterozygous mice was increased by application of Wnt3a or a GSK3 inhibitor. Sperm from mice that inducibly overexpressed the Wnt antagonist Dkk1 in the proximal epididymis showed reduced LRP6 activation and increased phosphorylation of PP1R2, and were less motile than those from control mice. Thus, the activation of Wnt signaling in sperm transiting through the epididymis promotes sperm maturation and motility.

S. Koch, S. P. Acebron, J. Herbst, G. Hatiboglu, C. Niehrs, Post-transcriptional Wnt signaling governs epididymal sperm maturation. Cell 163, 1225–1236 (2015). [PubMed]

E. M. De Robertis, D. Ploper, Sperm motility requires Wnt/GSK3 stabilization of proteins. Dev. Cell 35, 401–402 (2015). [Online Journal]