Phenotype of mice lacking functional Deleted in colorectal cancer (Dec) gene

Abstract

The DCC (Deleted in colorectal cancer) gene was first identified as a candidate for a tumour-suppressor gene on human chromosome 18q. More recently, in vitro studies in rodents have provided evidence that DCC might function as a receptor for the axonal chemoattractant netrin-1. Inactivation of the murine Dcc gene caused defects in axonal projections that are similar to those observed in netrin-1-deficient mice but did not affect growth, differentiation, morphogenesis or tumorigenesis in mouse intestine. These observations fail to support a tumour-suppressor function for Dcc, but are consistent with the hypothesis that DCC is a component of a receptor for netrin-1.

Axon guidance at the midline choice point

“…Consistent with the dose of Netrin-1 required to promote commissural axon outgrowth, Netrin-1 binds DCC with a dissociation constant (K d ) of 10 Ϫ8 M. Furthermore, an antibody against DCC blocks Netrin-1-dependent axon outgrowth in vitro (Keino-Masu et al, 1996). Most importantly, inactivation of netrin-1 or DCC (Fazeli et al, 1997) in mice leads to pathfinding defects that ultimately prevent most commissural axons from reaching the floor plate (see Fig. 5).…”

Induction of apoptosis and G2/M cell cycle arrest by DCC

“…RLU stands for relative light unit. Bar represents standard deviations knocked out (Fazeli et al, 1997). Mice homozygous for the Dcc 7 died within 24 h after birth, and showed defects in axonal projections.…”

Dependence receptors: a new paradigm in cell signaling and cancer therapy

“…The classic view for netrin-1 is that a gradient of this cue diffuses from a ventral spinal cord structure, the floor plate, and orients the growth of commissural axons as they extend circumferentially toward the ventral midline of the embryonic nervous system. The key role of DCC and netrin-1 in mediating axon outgrowth and pathfinding is supported by a large number of studies, particularly the analysis of DCC and netrin-1 knockout mice, which display similar defects in the central nervous system (Serafini et al, 1996;Fazeli et al, 1997). Such a dual role for a receptor, implicated during development and functioning as a putative tumor suppressor, seems to be a common trait for DRs.…”

“…Moreover, restoration of DCC expression can suppress tumorigenic growth properties in vitro or in nude mice (Klingelhutz et al, 1993;Velcich et al, 1999;Kato et al, 2000;Rodrigues et al, 2007). On the other hand, the fact that only 10-15% of colon cancers carry mutations in DCC and the lack of a tumor predisposing effect of DCC inactivation in mouse models (Fazeli et al, 1997) led some investigators to conclude that DCC had little or no biological role in colon cancer, and that its inactivation was an epiphenomenon. However, such a categoric judgment was partly due to the lack of understanding of the biological roles of DCC, which has since been compensated by its characterization as a DR (Grady, 2007).…”