• PMID: 26258444
• Gene Name: NF2
• Condition: Sperm capacitation
• Association: While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. Th
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Sperm capacitation

Merlin Isoforms 1 and 2 Both Act as Tumour Suppressors and Are Required for Optimal Sperm Maturation

Zoch A, Mayerl S, Schulz A, Greither T, Frappart L, Rübsam J, Heuer H, Giovannini M, Morrison H.

The tumour suppressor Merlin, encoded by the gene NF2, is frequently mutated in the autosomal dominant disorder neurofibromatosis type II, characterised primarily by the development of schwannoma and other glial cell tumours. However, NF2 is expressed in virtually all analysed human and rodent organs, and its deletion in mice causes early embryonic lethality. Additionally, NF2 encodes for two major isoforms of Merlin of unknown functionality. Specifically, the tumour suppressor potential of isoform 2 remains controversial. In this study, we used Nf2 isoform-specific knockout mouse models to analyse the function of each isoform during development and organ homeostasis. We found that both isoforms carry full tumour suppressor functionality and can completely compensate the loss of the other isoform during development and in most adult organs. Surprisingly, we discovered that spermatogenesis is strictly dependent on the presence of both isoforms. While the testis primarily expresses isoform 1, we noticed an enrichment of isoform 2 in spermatogonial stem cells. Deletion of either isoform was found to cause decreased sperm quality as observed by maturation defects and head/midpiece abnormalities. These defects led to impaired sperm functionality as assessed by decreased sperm capacitation. Thus, we describe spermatogenesis as a new Nf2-dependent process. Additionally, we provide for the first time in vivo evidence for equal tumour suppressor potentials of Merlin isoform 1 and isoform 2. FAU - Zoch, Ansgar AU - Zoch A AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany. FAU - Mayerl, Steffen AU - Mayerl S AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany. FAU - Schulz, Alexander AU - Schulz A AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany. FAU - Greither, Thomas AU - Greither T AD - Center for Reproductive Medicine and Andrology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany. FAU - Frappart, Lucien AU - Frappart L AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany. FAU - Rübsam, Juliane AU - Rübsam J AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany. FAU - Heuer, Heike AU - Heuer H AD - Leibniz Institute for Age Research-FLI Jena, Beutenbergstr. 11, D-07745 Jena, Germany; Leibniz Research Institute for Environmental Medicine, Auf'm Hennekamp 50, D-40225 Düsseldorf, Germany. FAU - Giovannini, Marco AU - Giovannini M AD - Center for Neural Tumor Research and Section on Genetics of Hereditary Ear Disorders, House Research Institute, University of California Los Angeles, Los Angeles, CA 90057, United States of America.