Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Serge Nef

ABSTRACT: we performed the analysis of SOX9-GFP+ cells purified from mouse embryonic testis at embryonic day E17.5 and Postnatal day 5 and analyzed the effect of the deletion of the Insulin receptor (InsR) and Igf1 receptor (Igf1R) by comparing double mutant and control SOX9+ Sertoli cells

ORGANISM(S): Mus musculus

SUBMITTER: Serge Nef

PROVIDER: E-MTAB-1192 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

An essential role for insulin and IGF1 receptors in regulating sertoli cell proliferation, testis size, and FSH action in mice.

Pitetti Jean-Luc JL Calvel Pierre P Zimmermann Céline C Conne Béatrice B Papaioannou Marilena D MD Aubry Florence F Cederroth Christopher R CR Urner Françoise F Fumel Betty B Crausaz Michel M Docquier Mylène M Herrera Pedro Luis PL Pralong François F Germond Marc M Guillou Florian F Jégou Bernard B Nef Serge S

Molecular endocrinology (Baltimore, Md.) 20130321 5

Testis size and sperm production are directly correlated to the total number of adult Sertoli cells (SCs). Although the establishment of an adequate number of SCs is crucial for future male fertility, the identification and characterization of the factors regulating SC survival, proliferation, and maturation remain incomplete. To investigate whether the IGF system is required for germ cell (GC) and SC development and function, we inactivated the insulin receptor (Insr), the IGF1 receptor (Igf1r) ...[more]

PMID: 23518924

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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

Serge Nef

Publications

An essential role for insulin and IGF1 receptors in regulating sertoli cell proliferation, testis size, and FSH action in mice.

Similar Datasets

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