An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland

Abstract

The Rho family small GTPase Cdc42 has been implicated in a wide range of cellular functions including the establishment of cell polarity and the remodeling of the actin cytoskeletal architecture, resulting in the tight regulation of cell growth and survival during developmental processes. The complete knock-out of Cdc42 in the mouse is embryonic-lethal, and its targeted deletion in various tissues has been shown to disrupt tissue homeostasis. Thus far, in most studies, the targeted deletion of Cdc42 occurred during embryogenesis. Here, we have used a conditional gene deletion strategy in mice to probe the specific role of Cdc42 during adult mammary gland function. Cdc42 conditional-knock-out females were unable to adequately nourish their pups, due to a disorganized epithelial compartment within their mammary glands. A closer examination showed that their mammary epithelial cells were not able to maintain functional alveolar lumens, due to an inability to establish normal apical/basal epithelial polarity, as well as proper cell-cell contacts. Loss of these essential epithelial characteristics led to a premature sloughing off of the Cdc42-null epithelial cells. Overall our findings demonstrate that Cdc42 plays essential roles in mammary gland function post pregnancy, where it helps to establish proper epithelial cell polarity and tissue homeostasis during lactation.

Cdc42 regulates junctional actin but not cell polarization in the Caenorhabditis elegans epidermis

“…For example, in the early Drosophila embryo, expressing dominant-negative Cdc42 blocks apicobasal polarization of the blastoderm epithelium ( Hutterer et al, 2004 ). Similarly, conditional Cdc42 knockout in several mammalian cell types, including 3D-cultured MDCK cells, mouse mammary epithelial cells, the developing kidney, and pancreatic epithelial cells, results in defective apicobasal polarity of tubular epithelia ( Martin-Belmonte et al, 2007 ; Kesavan et al, 2009 ; Elias et al, 2015 ; Druso et al, 2016 ). However, these and other studies did not examine the initial stages of epithelial polarization as it unfolded using time-lapse microscopy, leaving it unclear whether the observed polarity phenotypes result from a failure to initially establish polarity, or rather a rapid loss of polarity caused by defects in its maintenance.…”

Endocytosis in proliferating, quiescent and terminally differentiated cells

“…Mechanistically, E-cadherin uptake at AJs requires the endocytic proteins CIP4, also known as TRIP10) and dynamin 2 (hereafter called dynamin), as well as local actin polymerization that is mediated by Cdc42, Arf6, N-WASP and Arp2/3 (Druso et al, 2016;Georgiou et al, 2008;Leibfried et al, 2008;Palacios et al, 2002). The precise endocytic pathway is still unclear, but these are molecular factors that act both in CME and in FEME (Chan Wah Hak et al, 2018;Taylor et al, 2011).…”

Phenotypic characterisation of breast cancer: the role of CDC42

“…CDC42 is expressed at low levels in normal breast tissue and elevated in breast carcinomas [ 5 ], with an essential role in normal mammary development [ 6 ]. Despite the importance of the Rho-GTPase pathway in BC, CDC42 protein expression has not been evaluated in a large cohort of BCs with clinical outcome data.…”