GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation.
Urogenital tract abnormalities are among the most common congenital defects in humans. Male urogenital development requires Hedgehog-GLI signaling and testicular hormones, but how these pathways interact is unclear. We found that Gli3XtJ mutant mice exhibit cryptorchidism and hypospadias due to loca...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2020-06-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1008810 |
| _version_ | 1819028204344573952 |
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| author | Anbarasi Kothandapani Samantha R Lewis Jessica L Noel Abbey Zacharski Kyle Krellwitz Anna Baines Stephanie Winske Chad M Vezina Elena M Kaftanovskaya Alexander I Agoulnik Emily M Merton Martin J Cohn Joan S Jorgensen |
| author_facet | Anbarasi Kothandapani Samantha R Lewis Jessica L Noel Abbey Zacharski Kyle Krellwitz Anna Baines Stephanie Winske Chad M Vezina Elena M Kaftanovskaya Alexander I Agoulnik Emily M Merton Martin J Cohn Joan S Jorgensen |
| author_sort | Anbarasi Kothandapani |
| collection | DOAJ |
| description | Urogenital tract abnormalities are among the most common congenital defects in humans. Male urogenital development requires Hedgehog-GLI signaling and testicular hormones, but how these pathways interact is unclear. We found that Gli3XtJ mutant mice exhibit cryptorchidism and hypospadias due to local effects of GLI3 loss and systemic effects of testicular hormone deficiency. Fetal Leydig cells, the sole source of these hormones in developing testis, were reduced in numbers in Gli3XtJ testes, and their functional identity diminished over time. Androgen supplementation partially rescued testicular descent but not hypospadias in Gli3XtJ mutants, decoupling local effects of GLI3 loss from systemic effects of androgen insufficiency. Reintroduction of GLI3 activator (GLI3A) into Gli3XtJ testes restored expression of Hedgehog pathway and steroidogenic genes. Together, our results show a novel function for the activated form of GLI3 that translates Hedgehog signals to reinforce fetal Leydig cell identity and stimulate timely INSL3 and testosterone synthesis in the developing testis. In turn, exquisite timing and concentrations of testosterone are required to work alongside local GLI3 activity to control development of a functionally integrated male urogenital tract. |
| first_indexed | 2024-12-21T05:54:39Z |
| format | Article |
| id | doaj.art-c4d27519870641df92699837de73e702 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T05:54:39Z |
| publishDate | 2020-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-c4d27519870641df92699837de73e7022022-12-21T19:13:54ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042020-06-01166e100881010.1371/journal.pgen.1008810GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation.Anbarasi KothandapaniSamantha R LewisJessica L NoelAbbey ZacharskiKyle KrellwitzAnna BainesStephanie WinskeChad M VezinaElena M KaftanovskayaAlexander I AgoulnikEmily M MertonMartin J CohnJoan S JorgensenUrogenital tract abnormalities are among the most common congenital defects in humans. Male urogenital development requires Hedgehog-GLI signaling and testicular hormones, but how these pathways interact is unclear. We found that Gli3XtJ mutant mice exhibit cryptorchidism and hypospadias due to local effects of GLI3 loss and systemic effects of testicular hormone deficiency. Fetal Leydig cells, the sole source of these hormones in developing testis, were reduced in numbers in Gli3XtJ testes, and their functional identity diminished over time. Androgen supplementation partially rescued testicular descent but not hypospadias in Gli3XtJ mutants, decoupling local effects of GLI3 loss from systemic effects of androgen insufficiency. Reintroduction of GLI3 activator (GLI3A) into Gli3XtJ testes restored expression of Hedgehog pathway and steroidogenic genes. Together, our results show a novel function for the activated form of GLI3 that translates Hedgehog signals to reinforce fetal Leydig cell identity and stimulate timely INSL3 and testosterone synthesis in the developing testis. In turn, exquisite timing and concentrations of testosterone are required to work alongside local GLI3 activity to control development of a functionally integrated male urogenital tract.https://doi.org/10.1371/journal.pgen.1008810 |
| spellingShingle | Anbarasi Kothandapani Samantha R Lewis Jessica L Noel Abbey Zacharski Kyle Krellwitz Anna Baines Stephanie Winske Chad M Vezina Elena M Kaftanovskaya Alexander I Agoulnik Emily M Merton Martin J Cohn Joan S Jorgensen GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. PLoS Genetics |
| title | GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. |
| title_full | GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. |
| title_fullStr | GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. |
| title_full_unstemmed | GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. |
| title_short | GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. |
| title_sort | gli3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation |
| url | https://doi.org/10.1371/journal.pgen.1008810 |
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