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Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1
Ron Firestein, … , Marco Conti, Michael L. Cleary
Ron Firestein, … , Marco Conti, Michael L. Cleary
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1165-1172. https://doi.org/10.1172/JCI12589.
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Article Genetics Article has an altmetric score of 3

Male infertility, impaired spermatogenesis, and azoospermia in mice deficient for the pseudophosphatase Sbf1

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Abstract

Pseudophosphatases display extensive sequence similarities to phosphatases but harbor amino acid alterations in their active-site consensus motifs that render them catalytically inactive. A potential role in substrate trapping or docking has been proposed, but the specific requirements for pseudophosphatases during development and differentiation are unknown. We demonstrate here that Sbf1, a pseudophosphatase of the myotubularin family, is expressed at high levels in seminiferous tubules of the testis, specifically in Sertoli’s cells, spermatogonia, and pachytene spermatocytes, but not in postmeiotic round spermatids. Mice that are nullizygous for Sbf1 exhibit male infertility characterized by azoospermia. The onset of the spermatogenic defect occurs in the first wave of spermatogenesis at 17 days after birth during the synchronized progression of pachytene spermatocytes to haploid spermatids. Vacuolation of the Sertoli’s cells is the earliest observed phenotype and is followed by reduced formation of spermatids and eventual depletion of the germ cell compartment in older mice. The nullizygous phenotype in conjunction with high-level expression of Sbf1 in premeiotic germ cells and Sertoli’s cells is consistent with a crucial role for Sbf1 in transition from diploid to haploid spermatocytes. These studies demonstrate an essential role for a pseudophosphatase and implicate signaling pathways regulated by myotubularin family proteins in spermatogenesis and germ cell differentiation.

Authors

Ron Firestein, Peter L. Nagy, Megan Daly, Phil Huie, Marco Conti, Michael L. Cleary

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Figure 3

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Targeted disruption of the Sbf1 gene. (a) Schematic depiction of the Sbf...
Targeted disruption of the Sbf1 gene. (a) Schematic depiction of the Sbf1 protein, gene, targeting construct, and recombined allele. Conserved motifs present in Sbf1 include an N-terminal Rab GEF homology domain, internal MTM homology motifs, and a C-terminal PH domain. Following homologous recombination, a Pgk-Neo cassette replaces Sbf1 exons 21–28, which encode amino acids 653–1120 of the Sbf1 protein as indicated. Locations are shown for external probes A and B used for genotype analyses. Restriction enzyme sites: E, EcoRI; X, XhoI; S, SacI; H, HindIII; B, BamH1. (b) Southern blot analysis of genomic DNA isolated from wild-type (+/+), Sbf1+/– (+/–), and Sbf1–/– (–/–) mice. Probes are indicated below the respective panels. (c) Western blot analysis of brain extracts of wild-type (+/+), Sbf1+/– (+/–), or Sbf1–/– (–/–) mice. Primary Ab’s (indicated below panels) consisted of mAb’s specific for the N-terminal (mAb 8) or C-terminal (mAb 68) portions of Sbf1. Faint bands in some lanes at 150 kDa represent apparent Sbf1 degradation products.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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