Notum-flox Mouse

Notum, a palmitoleoyl-protein carboxylesterase, is a negative regulator of the Wnt signaling pathway. It acts by removing an essential palmitoleate group from Wnt proteins, thus inhibiting Wnt-FZD receptor-ligand interactions [3,4]. The Wnt signaling pathway is crucial for many cellular processes in development and adult mammalian biology, making Notum's role significant in various biological contexts [5].

In colorectal cancer, Apc-mutant cells highly express Notum. Conditioned medium from these cells suppresses wild-type organoid growth in a NOTUM-dependent manner. Genetic or pharmacological inhibition of NOTUM abrogates the ability of Apc-mutant cells to expand and form intestinal adenomas, indicating its role in the early stages of mutation fixation [1]. In aged intestinal epithelium, Notum produced by Paneth cells decreases stem-ness-maintaining Wnt signaling, impairing regeneration. Genetic targeting or pharmacological inhibition of Notum restores the function of aged intestinal organoids and enhances the regenerative capacity of aged stem cells [2]. In advanced colorectal cancer, NOTUM has different roles depending on the mutation landscape. In APC-null adenomas, it has tumour-suppressive activity, but upon P53 loss and progression to adenocarcinoma, it becomes an oncogene. Pharmacological inhibition of NOTUM effectively arrests primary adenocarcinoma growth and inhibits metastasis [4].

In conclusion, Notum plays a key role in modulating Wnt signaling, which is vital for multiple biological processes. Through gene-knockout or conditional-knockout mouse models and other loss-of-function experiments, Notum has been shown to be involved in disease conditions such as colorectal cancer and age-related intestinal epithelium regeneration decline. Understanding Notum's function provides potential therapeutic strategies for these diseases.