A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function
Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/15015 |
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| author | Anne-Louise Gannon Annalucia L. Darbey Grace Chensee Ben M. Lawrence Liza O’Donnell Joanna Kelso Natalie Reed Shanmathi Parameswaran Sarah Smith Lee B. Smith Diane Rebourcet |
| author_facet | Anne-Louise Gannon Annalucia L. Darbey Grace Chensee Ben M. Lawrence Liza O’Donnell Joanna Kelso Natalie Reed Shanmathi Parameswaran Sarah Smith Lee B. Smith Diane Rebourcet |
| author_sort | Anne-Louise Gannon |
| collection | DOAJ |
| description | Glucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production. However, endogenous glucocorticoids are produced by the adrenal and within the testis, but whether their action on GR in Leydig cells regulates steroidogenesis is unknown. This study aimed to define the role of endogenous GR signalling in adult Leydig cells. We developed and compared two models; an inducible Cre transgene driven by expression of the <i>Cyp17a1</i> steroidogenic gene (<i>Cyp17</i>-iCre) that depletes GR during development and a viral vector-driven Cre (AAV9-Cre) to deplete GR in adulthood. The delivery of AAV9-Cre ablated GR in adult mouse Leydig cells depleted Leydig cell GR more efficiently than the <i>Cyp17</i>-iCre model. Importantly, adult depletion of GR in Leydig cells caused reduced expression of luteinising hormone receptor (<i>Lhcgr</i>) and of steroidogenic enzymes required for normal androgen production. These findings reveal that Leydig cell GR signalling plays a physiological role in the testis and highlight that a normal balance of glucocorticoid activity in the testis is important for steroidogenesis. |
| first_indexed | 2024-03-09T17:45:25Z |
| format | Article |
| id | doaj.art-51831e7ec93d4cdba18e14569e3ea42c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:45:25Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-51831e7ec93d4cdba18e14569e3ea42c2023-11-24T11:11:45ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231501510.3390/ijms232315015A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell FunctionAnne-Louise Gannon0Annalucia L. Darbey1Grace Chensee2Ben M. Lawrence3Liza O’Donnell4Joanna Kelso5Natalie Reed6Shanmathi Parameswaran7Sarah Smith8Lee B. Smith9Diane Rebourcet10College of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaCollege of Engineering, Science and Environment, The University of Newcastle, Callaghan, NSW 2308, AustraliaGlucocorticoids are steroids involved in key physiological processes such as development, metabolism, inflammatory and stress responses and are mostly used exogenously as medications to treat various inflammation-based conditions. They act via the glucocorticoid receptor (GR) expressed in most cells. Exogenous glucocorticoids can negatively impact the function of the Leydig cells in the testis, leading to decreased androgen production. However, endogenous glucocorticoids are produced by the adrenal and within the testis, but whether their action on GR in Leydig cells regulates steroidogenesis is unknown. This study aimed to define the role of endogenous GR signalling in adult Leydig cells. We developed and compared two models; an inducible Cre transgene driven by expression of the <i>Cyp17a1</i> steroidogenic gene (<i>Cyp17</i>-iCre) that depletes GR during development and a viral vector-driven Cre (AAV9-Cre) to deplete GR in adulthood. The delivery of AAV9-Cre ablated GR in adult mouse Leydig cells depleted Leydig cell GR more efficiently than the <i>Cyp17</i>-iCre model. Importantly, adult depletion of GR in Leydig cells caused reduced expression of luteinising hormone receptor (<i>Lhcgr</i>) and of steroidogenic enzymes required for normal androgen production. These findings reveal that Leydig cell GR signalling plays a physiological role in the testis and highlight that a normal balance of glucocorticoid activity in the testis is important for steroidogenesis.https://www.mdpi.com/1422-0067/23/23/15015glucocorticoid receptorandrogensleydig cellsAAV9steroidogenesis |
| spellingShingle | Anne-Louise Gannon Annalucia L. Darbey Grace Chensee Ben M. Lawrence Liza O’Donnell Joanna Kelso Natalie Reed Shanmathi Parameswaran Sarah Smith Lee B. Smith Diane Rebourcet A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function International Journal of Molecular Sciences glucocorticoid receptor androgens leydig cells AAV9 steroidogenesis |
| title | A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function |
| title_full | A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function |
| title_fullStr | A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function |
| title_full_unstemmed | A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function |
| title_short | A Novel Model Using AAV9-Cre to Knockout Adult Leydig Cell Gene Expression Reveals a Physiological Role of Glucocorticoid Receptor Signalling in Leydig Cell Function |
| title_sort | novel model using aav9 cre to knockout adult leydig cell gene expression reveals a physiological role of glucocorticoid receptor signalling in leydig cell function |
| topic | glucocorticoid receptor androgens leydig cells AAV9 steroidogenesis |
| url | https://www.mdpi.com/1422-0067/23/23/15015 |
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