GLI3 resides at the intersection of hedgehog and androgen action to promote male sex differentiation
| Autor: | Samantha R. Lewis, Elena M. Kaftanovskaya, Stephanie Winske, Chad M. Vezina, Martin J. Cohn, Anbarasi Kothandapani, Anna Baines, Jessica Noel, Abbey Zacharski, Emily M. Merton, Alexander I. Agoulnik, Joan S. Jorgensen, Kyle Krellwitz |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research Embryology Sex Differentiation QH426-470 Biochemistry Mice 0302 clinical medicine Cell Signaling Cryptorchidism Medicine and Health Sciences Morphogenesis Insulin Testosterone Testes Lipid Hormones Testicular Hormones Genetics (clinical) 0303 health sciences Sexual Differentiation Leydig cell Gene Expression Regulation Developmental Leydig Cells Cell Differentiation Hedgehog signaling pathway medicine.anatomical_structure embryonic structures Androgens Male sex differentiation Anatomy Genital Anatomy Signal Transduction Research Article medicine.medical_specialty animal structures medicine.drug_class Mice Transgenic Nerve Tissue Proteins Biology 03 medical and health sciences Zinc Finger Protein Gli3 Internal medicine medicine Genetics Animals Humans Hedgehog Proteins Molecular Biology Hedgehog Ecology Evolution Behavior and Systematics 030304 developmental biology Sexual differentiation Embryos Reproductive System Proteins Biology and Life Sciences Cell Biology Androgen Hormones Disease Models Animal Endocrinology Mutation Hedgehog Signaling Androgen insufficiency 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | PLoS Genetics, Vol 16, Iss 6, p e1008810 (2020) PLoS Genetics |
| ISSN: | 1553-7404 1553-7390 |
| Popis: | 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. Author summary Disorders in male sex differentiation (DSD) are among the most common defects in all live births, yet in many cases, pediatric patient families are reluctant to address the issue and endure lifelong consequences. Urogenital tract development, as in many organ systems, depends on exquisite timing among layers of a number of signaling pathways. Here, we show that interactions between the hedgehog and androgen signaling pathways are required for the development of internal and external male sex characteristics, but results for each tissue is distinct. This new knowledge will aid in discovering the means by which congenital malformations might occur, identify potential developmental targets that might be vulnerable to environmental exposures, and promote new ideas for how they might be prevented. |
| Databáze: | OpenAIRE |
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