A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice

Weeble mutant mice have severe locomotor instability and significant neuron al loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosph ate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion resul ts in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca2+ release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in eit her may account for the neuronal loss of weeble mice. Although other mutati ons in phosphoinositide enzymes are associated with synaptic defects withou t neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.