Pde8b haploinsufficiency in mice is associated with modest adrenal defects, impaired steroidogenesis, and male infertility, unaltered by concurrent PKA or Wnt activation

Author(s):Show less -

Leal, Leticia Ferro ^{[1, 2, 3, 4]} ; Szarek, Eva ^[4] ; Berthon, Annabel ^[4] ; Nesterova, Maria ^[4] ; Faucz, Fabio R. ^[4] ; London, Edra ^[4] ; Mercier, Christopher ^[4] ; Abu-Asab, Mones ^[4] ; Starost, Matthew F. ^[5] ; Dye, Louis ^[6] ; Bilinska, Barbara ^[7] ; Kotula-Balak, Malgorzata ^[8] ; Antonini, Sonir R. ^[1] ; Stratakis, Constantine A. ^[4]

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, BR-14049900 Sao Paulo - Brazil

^[2] Barretos Canc Hosp, Mol Oncol Res Ctr, Barretos - Brazil

^[3] Dr Paulo Prata FACISB, Barretos Sch Hlth Sci, Barretos - Brazil

^[4] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet PDEGEN, NIH, Bethesda, MD 20892 - USA

^[5] NIH, Div Vet Resources, Bethesda, MD 20892 - USA

^[6] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, Microscopy & Imaging Core, NIH, Bethesda, MD 20892 - USA

^[7] Jagiellonian Univ Krakow, Inst Zool, Dept Endocrinol, Krakow - Poland

^[8] Agr Univ Krakow, Univ Ctr Vet Med, Krakow - Poland

• Document type: Journal article
• Source: Molecular and Cellular Endocrinology; v. 522, FEB 15 2021.
• Web of Science Citations: 0

Abstract

PDE8B, PRKAR1A and the Wnt/beta-catenin signaling are involved in endocrine disorders. However, how PDEB8B interacts with both Wnt and protein kinase A (PKA) signaling in vivo remains unknown. We created a novel Pde8b knockout mouse line (Pde8b(-/)(-)); Pde8b haploinsufficient (Pde8b(+/-)) mice were then crossed with mice harboring: (1) constitutive beta-catenin activation (Pde8b(+/)(-);Delta Cat) and (2) Prkar1a haploinsufficieny (Pde8b(+/-);Prkar1a(+/)(-)). Adrenals and testes from mice (3-12-mo) were evaluated in addition to plasma corticosterone, aldosterone and Dkk3 concentrations, and the examination of expression of steroidogenesis-, Wnt- and cAMP/PKA-related genes. Pde8b(-/-) male mice were infertile with down-regulation of the Wnt/beta-catenin pathway which did not change significantly in the Pde8b(+/-);Delta Cat mice. Prkarla haploinsufficiency also did not change the phenotype significantly. In vitro studies showed that PDE8B knockdown upregulated the Wnt pathway and increased proliferation in CTNNB1-mutant cells, whereas it downregulated the Wnt pathway in PRKAR1Amutant cells. These data support an overall weak, if any, role for PDE8B in adrenocortical tumorigenesis, even when co-altered with Wnt signaling or PKA upregulation; on the other hand, PDE8B appears to play a significant role in male fertility. (AU)

• FAPESP's process: 13/05337-3 - The interaction between Wnt canonical pathway with PRKAR1A and PDE8B in adrenocortical tumor development and/or progression by using a transgenic mouse model
• Grantee: Letícia Ferro Leal
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate