Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Testis-to-ovary reprogramming and testis regression after ablation of Sox9 in Sox8-/- mice

ABSTRACT: We used two Sertoli-cell-specific Cre lines: Wt1-CreERT2 and Sox9-CreERT2, to induce Sox9 ablation on a Sox8 -/- background in the adult testis. Sox9/8 double KO testes undergo testis-to-ovary genetic reprogramming and Sertoli-to-granulosa cell transdifferentiation.

INSTRUMENT(S): HPC services from the University of Granada (http://alhambra.ugr.es), Illumina HiSeq 2000

ORGANISM(S): Mus musculus

SUBMITTER: Miguel Burgos

PROVIDER: E-MTAB-4572 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration.

Barrionuevo Francisco J FJ Hurtado Alicia A Kim Gwang-Jin GJ Real Francisca M FM Bakkali Mohammed M Kopp Janel L JL Sander Maike M Scherer Gerd G Burgos Miguel M Jiménez Rafael R

eLife 20160621

The new concept of mammalian sex maintenance establishes that particular key genes must remain active in the differentiated gonads to avoid genetic sex reprogramming, as described in adult ovaries after Foxl2 ablation. Dmrt1 plays a similar role in postnatal testes, but the mechanism of adult testis maintenance remains mostly unknown. Sox9 and Sox8 are required for postnatal male fertility, but their role in the adult testis has not been investigated. Here we show that after ablation of Sox9 in ...[more]

PMID: 27328324

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Project description:Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular ageing. Sox9 (SRY-Box Transcription Factor 9) is a master regulator of chondrogenesis, also expressed in the vasculature, that has been implicated in vascular smooth muscle cell (VSMC) osteo-chondrogenic conversion. Here, we investigated the relationship between vascular ageing, calcification and Sox9-driven ECM regulation in VSMCs. Immunohistochemistry in human aortic samples showed that Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16. Analysis of Sox9 expression in vitro showed it was mechanosensitive with increased expression and nuclear translocation in senescent cells and on stiff matrices. Manipulation of Sox9 via overexpression and depletion, combined with atomic force microscopy (AFM) and proteomics, revealed that Sox9 regulates ECM stiffness and organisation by orchestrating changes in collagen expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs whereby senescent cells plated onto ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (LH3) was identified as a Sox9 target, and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles (EVs) and Sox9 promoted EV secretion, leading to increased LH3 deposition within the ECM. These findings identify cellular senescence and Sox9 as a key regulators of ECM stiffness during VSMC ageing and highlight a crucial role for ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle whereby cellular senescence and increased ECM stiffening promote Sox9 expression which drives further ECM modifications that act to accelerate vascular stiffening and cellular senescence.

Dataset Information

Testis-to-ovary reprogramming and testis regression after ablation of Sox9 in Sox8-/- mice

Publications

Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration.

Similar Datasets

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