UC San Diego

Formation of the mammalian brain requires the coordination of numerous events during embryonic development, the complexity of which is illustrated by the large number of defects that have been identified in humans. Analysis of both human genetic disorders and reverse genetically engineered mice have been invaluable in the endeavor to understand the molecular mechanisms underlying proper cortical development. Likewise, forward genetic screens have the potential of generating novel mouse models for human disorders, which can contribute by identifying novel genes and provide resources to investigate the molecular mechanisms of disease phenotypes. This study demonstrates that a genetic screen of ENU mutagenized mice identified a mouse pedigree that exhibits recessive primary microcephaly. Genetic mapping has identified a novel microcephaly locus for this mutation on chromosome 5qB1. Alternatively, doublecortin was identified as the gene disrupted in the human female disorder double cortex and the male disorder X-linked lissencephaly. This study identified spinophilin as a novel binding partner for doublecortin and used single and double knockouts of spinophilin and doublecortin to investigate the role of this interaction in cortical neurons. This approach allowed us to propose a novel model for microtubule condensation at the transition zone between the growth cone and neurite shaft, in this way helping to further our understanding of the role doublecortin plays in neuronal migration and axon outgrowth