Abstract

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.

Original languageEnglish
Article numberdev165324
JournalDevelopment
Volume145
Issue number18
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • Gilz
  • Mtorc1
  • Spermatogenesis
  • Spermatogonial stem cells
  • Tsc22d family

Cite this

@article{38f0a949cf834813be7a86ec88b7d1e6,
title = "GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance",
abstract = "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.",
keywords = "Gilz, Mtorc1, Spermatogenesis, Spermatogonial stem cells, Tsc22d family",
author = "La, {Hue M.} and Ai-Leen Chan and Legrand, {Julien M. D.} and Rossello, {Fernando J.} and Gangemi, {Christina G.} and Antonella Papa and Qiang Cheng and Morand, {Eric F.} and Hobbs, {Robin M.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1242/dev.165324",
language = "English",
volume = "145",
journal = "Development",
issn = "0950-1991",
publisher = "The Company of Biologists Ltd",
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}

GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance. / La, Hue M.; Chan, Ai-Leen; Legrand, Julien M. D.; Rossello, Fernando J.; Gangemi, Christina G.; Papa, Antonella; Cheng, Qiang; Morand, Eric F.; Hobbs, Robin M.

In: Development, Vol. 145, No. 18, dev165324, 01.09.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - GILZ-dependent modulation of mTORC1 regulates spermatogonial maintenance

AU - La, Hue M.

AU - Chan, Ai-Leen

AU - Legrand, Julien M. D.

AU - Rossello, Fernando J.

AU - Gangemi, Christina G.

AU - Papa, Antonella

AU - Cheng, Qiang

AU - Morand, Eric F.

AU - Hobbs, Robin M.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - 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.

AB - 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.

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KW - Mtorc1

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KW - Spermatogonial stem cells

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U2 - 10.1242/dev.165324

DO - 10.1242/dev.165324

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VL - 145

JO - Development

JF - Development

SN - 0950-1991

IS - 18

M1 - dev165324

ER -