Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development

Abstract

The int-1 proto-oncogene was first identified as a gene activated in virally induced mouse mammary tumours. Expression studies, however, suggest that the normal function of this gene may be in spermatogenesis and in the development of the central nervous system. Genes sharing sequence similarity with int-1 have been found throughout the animal kingdom. For example, int-1 has 54% amino-acid identity to the Drosophila segment polarity gene wingless (wg). Both the int-1 and wg gene products seem to be secreted proteins, presumably involved in cell-cell signalling. We have now explored the function of int-1 in the mouse by disrupting one of the two int-1 alleles in mouse embryo-derived stem cells using positive-negative selection. This cell line was used to generate a chimaeric mouse that transmitted the mutant allele to its progeny. Mice heterozygous for the int-1 null mutation are normal and fertile, whereas mice homozygous for the mutation may exhibit a range of phenotypes from death before birth to survival with severe ataxia. The latter pathology in mice and humans is often associated with defects in the cerebellum. Examination of int-1-/int-1- mice at several stages of embryogenesis revealed severe abnormalities in the development of the mesencephalon and metencephalon indicating a prominent role for the int-1 protein is in the induction of the mesencephalon and cerebellum.

Cancer stem cells in glioblastoma—molecular signaling and therapeutic targeting

“…Wnt-β-catenin signaling has clearly defined roles in both normal stem cells and cancer stem cells (Grigoryan et al, 2008). In brain, the Wnt signaling pathway regulates brain development as well as proliferation and selfrenewal of neural stem or progenitor cells in the fetal ventricular zone, the postnatal subventricular zone and hippocampus (McMahon et al, 1990;Thomas et al, 1990;Lie et al, 2005;Adachi et al, 2007;Kalani et al, 2008). The alterations of Wnt signaling pathway have been linked to medulloblastoma (Koch et al, 2001;Yokota et al, 2002).…”

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Indeed, mounting evidence gathered from functional studies of either Wnt ligands or their downstream signaling components, including the complex of receptors, have shown that in the developing brain Wnt signaling participates in patterning the midbrain-hindbrain boundary, which later on gives rise to the brainstem and the cerebellum ( McMahon and Bradley, 1990; Thomas and Capecchi, 1990;Thomas et al, 1991;McMahon et al, 1992;Hall et al, 2000), and forebrain derivatives such as the cerebral cortex, hippocampal formation and the amygdala (Grove et al, 1998;Lako et al, 1998;Lee et al, 2000;Houart et al, 2002;Maretto et al, 2003;Abu-Khalil et al, 2004;Zhou et al, 2004). Remarkably, embryonic transgenic mice expressing active stabilized forms of b-catenin in neuronal precursor cells developed gross enlargements of the cerebral cortex, hippocampus and amygdala Walsh, 2002, 2003).…”

Zebrafish E‐cadherin: Expression during early embryogenesis and regulation during brain development

“…When formed, the MHB displays organizer activities (Marin and Puelles, 1994;Martinez et al, 1991), generating signals that induce the development of cerebellum, tegmentum, and optic tectum. wnt1 mutations in mouse disrupt MHB development (McMahon and Bradley, 1990;McMahon et al, 1992;Thomas and Capecchi, 1990;Thomas et al, 1991), and wnt1 distributions suggest a similar role in MHB formation in zebrafish (Kelly and Moon, 1995), but mutations in the zebrafish wnt1 gene have not been identified. wnt1 mutations in mice expand E-cadherin and reduce ␣N-catenin expression domains in the developing diencephalon and mesencephalon (Shimamura et al, 1994).…”