Biology subjects

Sahut-Barnola, I.

Publications and source records attributed to Sahut-Barnola, I..

3 recordsLinked to original sources

bioRxiv2022

Loss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking zonal transdifferentiation

SUMOylation is a dynamic posttranslational modification, that provides fine-tuning of protein function involved in the cellular response to stress, differentiation, and tissue development. In the adrenal cortex, an emblematic endocrine organ that mediates adaptation to physiological demands, the SUMOylation gradient is inversely correlated with the gradient of cellular differentiation raising important questions about its role in functional zonation and the response to stress. Considering that SUMO-specific protease 2 (SENP2), a deSUMOylating enzyme, is upregulated by ACTH/PKA signalling within the zona Fasciculata (zF), we generated mice with adrenal-specific Senp2 loss to address these questions. Disruption of SENP2 activity in steroidogenic cells leads to specific hypoplasia of the zF, a blunted reponses to ACTH and isolated glucocorticoid deficiency. Mechanistically, overSUMOylation resulting from SENP2 loss shifts the balance between ACTH/PKA and WNT/{beta}-catenin signalling leading to repression of PKA activity and ectopic activation of {beta}-catenin. At the cellular level, this blocks transdifferentiation of {beta}-catenin-positive zona Glomerulosa cells into zF cells and sensitises them to premature apoptosis. Our findings indicate that the SUMO pathway is critical for adrenal homeostasis and stress responsiveness.

physiology↗

bioRxiv2022

Steroidogenic factor-1 lineage origin of skin lesions in Carney complex syndrome

Carney complex (CNC) is a rare familial multi-neoplastic syndrome predisposing to endocrine and non-endocrine tumors due to inactivating mutations of PRKAR1A leading to perturbations of the cAMP protein kinase A (PKA) signaling pathway. Skin lesions are the most common manifestation of CNC, including lentigines, blue nevi and cutaneous myxomas, in unusual locations such as oral and genital mucosa. Unlike endocrine disorders, the pathogenesis of skin lesions remains unexplained. Here, we show that embryonic invalidation of the Prkar1a gene in Steroidogenic Factor-1-expressing cells, leads to the development of familial skin pigmentation alterations reminiscent of those in patients. Immunohistological and molecular analyses coupled with genetic monitoring of recombinant cell lineages in mouse skin, suggest that familial lentiginosis and myxomas occurs in skin areas specifically enriched in dermal melanocytes. In lentigines and blue nevi-prone areas from mutant mice and patients, Prkar1a/PRKAR1A invalidation occurs in a subset of dermal fibroblasts capable of inducing, under the influence of PKA signaling, the production of pro-melanogenic EDN3 and HGF signals. Our model strongly suggests that the origin of the typical CNC cutaneous lesions is the result of non-cell-autonomous pro-melanogenic activity of a dermal fibroblast population sharing a community of origin with SF-1 lineage.

pathology↗

bioRxiv2020

PKA drives paracrine crisis and WNT4-dependent testis tumor in Carney complex

Large Cell Calcifying Sertoli Cell Tumors (LCCSCTs) are among the most frequent lesions occurring in Carney complex (CNC) male patients. Although they constitute a key diagnostic criterion for this rare multiple neoplasia syndrome resulting from inactivating mutations of the tumor suppressor PRKAR1A leading to unrepressed PKA activity, the LCCSCT pathogenesis and origin remain elusive. Mouse models targeting Prkar1a inactivation in all somatic populations or separately in each cell type were generated to decipher the molecular and paracrine networks involved in the CNC testis lesion induction. We demonstrate that Prkar1a mutation is required in both stromal and Sertoli cells for the occurrence of LCCSCT. Integrative analyses comparing transcriptomic, immunohistological data and phenotype of mutant mouse combinations led to understand the human LCCSCT pathogenesis and demonstrated unprecedented PKA-induced paracrine molecular circuits in which the aberrant WNT4 signal production is a limiting step in shaping intratubular lesions and tumor expansion both in mouse model and human CNC testes.

pathology↗