A genetic interaction between the APP and Dab1 genes influences brain development.
The Dab1 docking protein is required for the proper organization of brain laminae and for a signal transduction pathway initiated by Reelin binding to the ApoER2 and VLDLR receptors on the cell surface of neurons. Dab1 physically interacts with APP; however, it is not known whether the APP gene influences Dab1 function. Here we demonstrate a genetic interaction between Dab1 and APP. Dab1-hypomorphic animals have neuronal ectopias in the neocortex and reduced cerebellar volume, possibly a consequence of Purkinje cell misplacement. These phenotypes are exacerbated in transgenic animals overexpressing a mutant form of APP, APP(swe), which is characterized by increased processing at the beta-secretase site. The Dab1-hypomorphic phenotype is improved in the cerebellum of animals that are deficient for APP. Together this suggests that APP expression constrains the consequences of Dab1 activity during brain development.
Pramatarova
Albéna
A
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, 35 Convent Dr., Bethesda, MD 20892, USA.
Chen
Kelian
K
Howell
Brian W
BW
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000033:anatomy & histology* / Q000254:growth & development*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D000091042:Reelin Protein
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D000091042:Reelin Protein; C000717128:Reln protein, mouse