• PMID: 30126904
• Gene Name: TSC22D3
• Condition: Regulates spermatogonial maintenance
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Regulates spermatogonial maintenance

GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance

La HM, Chan AL, Legrand JMD, Rossello FJ, Gangemi CG, Papa A, Cheng Q, Morand EF, Hobbs RM.

Male fertility is dependent on spermatogonial stem cells (SSCs) that self-renew and produce differentiating germ cells. Growth factors produced within the testis are essential for SSC maintenance but intrinsic factors that dictate the SSC response to these stimuli are poorly characterised. Here, we have studied the role of GILZ, a TSC22D family protein and spermatogenesis regulator, in spermatogonial function and signalling. Although broadly expressed in the germline, GILZ was prominent in undifferentiated spermatogonia and Gilz deletion in adults resulted in exhaustion of the GFRα1(+) SSC-containing population and germline degeneration. GILZ loss was associated with mTORC1 activation, suggesting enhanced growth factor signalling. Expression of deubiquitylase USP9X, an mTORC1 modulator required for spermatogenesis, was disrupted in Gilz mutants. Treatment with an mTOR inhibitor rescued GFRα1(+) spermatogonial failure, indicating that GILZ-dependent mTORC1 inhibition is crucial for SSC maintenance. Analysis of cultured undifferentiated spermatogonia lacking GILZ confirmed aberrant activation of ERK MAPK upstream mTORC1 plus USP9X downregulation and interaction of GILZ with TSC22D proteins. Our data indicate an essential role for GILZ-TSC22D complexes in ensuring the appropriate response of undifferentiated spermatogonia to growth factors via distinct inputs to mTORC1. CI - © 2018. Published by The Company of Biologists Ltd. FAU - La, Hue M AU - La HM AUID- ORCID: 0000-0003-4549-7017 AD - Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia. AD - Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Chan, Ai-Leen AU - Chan AL AD - Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia. AD - Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Legrand, Julien M D AU - Legrand JMD AD - Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia. AD - Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Rossello, Fernando J AU - Rossello FJ AD - Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia. AD - Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Gangemi, Christina G AU - Gangemi CG AD - Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria 3800, Australia. AD - Development and Stem Cells Program, Monash Biomedicine Discovery Institute and Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Papa, Antonella AU - Papa A AD - Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria 3800, Australia. FAU - Cheng, Qiang AU - Cheng Q AUID- ORCID: 0000-0002-5066-5583 AD - Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria 3800, Australia. FAU - Morand, Eric F AU - Morand EF AD - Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria 3800, Australia.