GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation

Autoři: Anbarasi Kothandapani aff001;  Samantha R. Lewis aff001;  Jessica L. Noel aff001;  Abbey Zacharski aff001;  Kyle Krellwitz aff001;  Anna Baines aff001;  Stephanie Winske aff001;  Chad M. Vezina aff001;  Elena M. Kaftanovskaya aff002;  Alexander I. Agoulnik aff002;  Emily M. Merton aff003;  Martin J. Cohn aff003;  Joan S. Jorgensen aff001
Působiště autorů: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America aff001;  Department of Human and Molecular Genetics, Florida International University, Miami, Florida, United States of America aff002;  Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States of America aff003
Vyšlo v časopise: GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008810
Kategorie: Research Article


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.

Klíčová slova:

Androgens – Cell differentiation – Embryos – Genital anatomy – Hedgehog signaling – Sexual differentiation – Testes – Testosterone


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