Effect of Shoc2 Elimination in Urinary Bladder Function

Sibel Sari* (ORCID: https://orcid.org/0000-0002-2505-5804) and Pablo Rodriguez-Viciana (ORCID: https://orcid.org/0000-0002-8846-543X)

*1Abdullah Gul University, Faculty of Life and Natural Sciences, Molecular Biology and Genetics, Kayseri, Turkey. 2University College London (UCL) Cancer Institute, London, UK

*Corresponding author e-mail: sibel.sari@agu.edu.tr

Abstract

The RAS-RAF-MEK-ERK signalling pathway plays an important role throughout mammalian development, from embryogenesis to tissue-specific cellular homeostasis and its aberrant activation is a major driver of human cancer. Mouse models have highly improved our current understanding of the RAS-ERK pathway in physiological and pathological contexts.

RAF activation is a complex process that involves multiple regulatory steps in addition to RAS binding. Key among them is the dephosphorylation of a conserved inhibitory site (S259-RAF1, S365-BRAF) by a phosphatase complex comprised of SHOC2, MRAS and PP1 (SHOC2 complex).
In order to study the role of Shoc2 in tissue homeostasis we have generated a mouse model of conditional Shoc2 inactivation. Shoc2 knock-out (KO) mice are embryonic lethal indicating Shoc2 function is required during mouse development. To study Shoc2 function in adult tissue homeostasis, Shoc2 KO mice were crossed with animals carrying an inducible ubiquitously expressed CreERT2 recombinase (R26-CreERT2). Treatment with tamoxifen leads to efficient recombination (>80%) in all tissues examined except brain.

In this study, we discovered a sexually dimorphic role of Shoc2 in urinary function, with male, but not female KO mice developing severely distended bladders full of urine. No significant histopathological change such as epithelial hyperplasia or tumour formation were detected in bladder and urethra of Shoc2 KO mice. In addition, no renal damage is obvious in mice with enlarged bladders. Also, the prostate glands of Shoc2 KO mice were of normal size and appearance without any obvious histological abnormalities. Furthermore, affected mice appeared able to urinate normally and water consumption was unaltered. As a result, urethral or prostate obstruction appear unlikely to be responsible for enlarged bladders of Shoc2 KO mice.

Keywords: Shoc2, Transgenic Mouse Models, Urinary Bladder