Reference SummaryZoch A, PLoS One 2015;10(8):e0129151

Title

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

Authors

Zoch A; Mayerl S; Schulz A; Greither T; Frappart L; Rubsam J; Heuer H; Giovannini M; Morrison H

Journal

PLoS One

Volume

10

Issue

8

Year

2015

Pages

e0129151

Abstract

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.

Links

26258444 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
C57BL/6 Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

0

C57BL/6-Nf2tm1Gvn Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

5

C57BL/6-Nf2tm2Gvn Connective tissue - Fibroblast fibrosarcoma Connective tissue - Fibroblast

0

C57BL/6 Kidney adenocarcinoma Kidney

0

C57BL/6-Nf2tm1Gvn Kidney adenocarcinoma Kidney

0

C57BL/6-Nf2tm2Gvn Kidney adenocarcinoma Kidney

9.09

C57BL/6 Kidney cyst Kidney

5.56

C57BL/6-Nf2tm1Gvn Kidney cyst Kidney

5

C57BL/6-Nf2tm2Gvn Kidney cyst Kidney

0

C57BL/6 Leukocyte lymphoma Leukocyte

5.56

C57BL/6-Nf2tm1Gvn Leukocyte lymphoma Leukocyte

10

C57BL/6-Nf2tm2Gvn Leukocyte lymphoma Leukocyte

27.27

C57BL/6 Liver hepatoma Liver

11.11

C57BL/6-Nf2tm1Gvn Liver hepatoma Liver

5

C57BL/6-Nf2tm2Gvn Liver hepatoma Liver

0

C57BL/6 Lung adenoma Lung

5.56

C57BL/6-Nf2tm1Gvn Lung adenoma Lung

0

C57BL/6-Nf2tm2Gvn Lung adenoma Lung

0

C57BL/6 (Unspecified organ) tumor (Unspecified organ)

observed

C57BL/6-Nf2tm1Gvn (Unspecified organ) tumor (Unspecified organ)

observed

C57BL/6-Nf2tm2Gvn (Unspecified organ) tumor (Unspecified organ)

observed