Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway effecting intracellular Ca2 release, but are also involved in cell cycle regulation through binding the Akt proto-oncogene; dysfunction in either or both is likely responsible for the neuronal loss of weeble mice. A similar gene Inpp4b is known to be expressed in other tissues and could be compensating for the loss of Inpp4a in tissue where its function is needed. This proposal aims to determine the mechanism of cellular pathology of the neurons in the weeble mouse. A comparative expression analysis of the two genes, Inpp4a and Inpp4b, thorough development will be performed and that information will be compared to the actual neural pathology. This information will help to determine whether cells are dying themselves, causing the death of their neighbors, or both. Additionally, we will investigate a likely mechanism for neuronal loss involving the hyperactivation of the Akt proto-oncogene. Together these aims will provide an understanding of precisely where, when and why neurons are lost due to the loss of Inpp4a function.
|Shin, Hye-Won; Hayashi, Mitsuko; Christoforidis, Savvas et al. (2005) An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. J Cell Biol 170:607-18|