Inhibition of SRY-Calmodulin Complex Formation Induces Ectopic Expression of Ovarian Cell Markers in Developing XY Gonads
| Autor: | Francis Poulat, Daniel Peter Czech, Peter Koopman, Anthony Argentaro, Andrew H. Sinclair, Vincent R. Harley, Helena Sim, Stefan Bagheri-Fam, Brigitte Boizet-Bonhoure |
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| Přispěvatelé: | Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Forkhead Box Protein L2
Male Mice 0302 clinical medicine Endocrinology Chlorocebus aethiops Testis ComputingMilieux_MISCELLANEOUS Spermatic Cord 0303 health sciences Sexual differentiation in humans Forkhead Transcription Factors SOX9 Transcription Factor Recombinant Proteins Forkhead box L2 medicine.anatomical_structure Testis determining factor COS Cells geographic locations Transcriptional Activation endocrine system medicine.medical_specialty animal structures Gonad Active Transport Cell Nucleus SOX9 Biology Y chromosome 03 medical and health sciences Organ Culture Techniques Calmodulin Internal medicine parasitic diseases medicine Animals Spermatogenesis Transcription factor 030304 developmental biology Cell Nucleus [SDV.GEN]Life Sciences [q-bio]/Genetics social sciences Sex Determination Processes Embryo Mammalian Antigens Differentiation Sex-Determining Region Y Protein Calmodulin-Binding Proteins Ectopic expression Thrombospondins 030217 neurology & neurosurgery |
| Zdroj: | Endocrinology Endocrinology, Endocrine Society, 2011, 152 (7), pp.2883-2893. ⟨10.1210/en.2010-1475⟩ |
| ISSN: | 0013-7227 |
| DOI: | 10.1210/en.2010-1475⟩ |
| Popis: | The transcription factor sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, because mutations in SRY cause disorders of sex development in XY individuals. During gonadal development, Sry in pre-Sertoli cells activates Sox9 gene transcription, committing the fate of the bipotential gonad to become a testis rather than an ovary. The high-mobility group domain of human SRY contains two independent nuclear localization signals, one bound by calmodulin (CaM) and the other by importin-β. Although XY females carry SRY mutations in these nuclear localization signals that affect SRY nuclear import in transfected cells, it is not known whether these transport mechanisms are essential for gonadal development and sex determination. Here, we show that mouse Sry protein binds CaM and that a CaM antagonist reduces CaM binding, nuclear accumulation, and transcriptional activity of Sry in transfected cells. CaM antagonist treatment of cultured, sexually indifferent XY mouse fetal gonads led to reduced expression of the Sry target gene Sox9, defects in testicular cord formation, and ectopic expression of the ovarian markers Rspondin1 and forkhead box L2. These results indicate the importance of CaM for SRY nuclear import, transcriptional activity, testis differentiation, and sex determination. |
| Databáze: | OpenAIRE |
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