RT Journal Article
SR Electronic
T1 Steroidogenic factor-1 lineage origin of skin lesions in Carney complex syndrome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.26.477839
DO 10.1101/2022.01.26.477839
A1 Isabelle Sahut-Barnola
A1 A-Marie Lefrancois-Martinez
A1 Damien Dufour
A1 Jean-Marie Botto
A1 Crystal Kamilaris
A1 Fabio R. Faucz
A1 Constantine A. Stratakis
A1 Pierre Val
A1 Antoine Martinez
YR 2022
UL http://biorxiv.org/content/early/2022/01/28/2022.01.26.477839.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.