Lissencephaly: Smooth Brains, Neuronal Migration and Neurogenesis
Our laboratory has provided important insights into the genes and pathways responsible for human neuronal migration defects, produced the first mouse models of these defects, and defined several components of the pathways through which these human disease genes act. For example, children with lissencephaly, or smooth brain, display either lissencephaly alone (isolated lissencephaly sequence, ILS) or the more severe defect Miller-Dieker syndrome (MDS), where children display more severe lissencephaly as well as facial dysmorphisms. Many of these children display heterozygous deletions in human chromosome 17p13, a region that includes the gene LIS1. LIS1 regulates the function of the microtubule motor dynein as part of an evolutionarily conserved complex (Sasaki et al. 2000). Several years ago, we produced an allelic series of Lis1 mutant mice and in several studies demonstrated that these mice are excellent models of the human neuronal migration defect ILS (Hirotsune et al. 1998, Gambello et al. 2003). The gene for 14-3-3(epsilon), an adapter for serine-threonine phosphoproteins, is closely linked to LIS1 in human 17p13. We demonstrated that 14-3-3(epsilon) knock-out mice display neuronal migration defects via components of the Lis1 pathway (Toyo-oka et al. 2003). This study and a collaborative study in human patients with MDS demonstrated that loss of LIS1 and 14-3-3(epsilon) together contributes to the more severe grades of lissencephaly seen in MDS patients compared to patients with ILS. More recently, while studying the effect of complete loss of Lis1 in mice using conditional knock-outs, we uncovered a critical role for Lis1 in regulating neurogenesis prior to neuronal migration. We found that Lis1 is essential for neuroepithelial stem cell proliferation by controlling spindle orientation and symmetrical division, defining an unexpected sensitivity for symmetrical division in these early progenitors (Yingling et al. 2008). Future experiments will examine the consequences of dysregulation of spindle orientation throughout brain development as well as the cell biological and biochemical mechanisms responsible for these defects. We will continue to study the cell biological and biochemical mechanisms responsible for neuronal migration defects using these and other mouse models produced in the lab.

Dishevelled: Crossroads of Wnt and PCP Pathways
Our laboratory has made mice with mutations in each of the three Dishevelled genes, which code for a protein critical for two intersecting developmental pathways, the Wnt and planar cell polarity (PCP) pathways. Dishevelled-1 (Dvl1) mutant mice were the first mice found to display mammalian social behavior defects (Lijam et al. 1997), and may be a model for human neuropsychiatric diseases such as autism and schizophrenia. We found that most Dvl2 mutant mice die at birth from outflow tract heart defects, and display somite segmentation defects (Hamblet et al. 2002). More recently, our laboratory demonstrated that a conserved planar cell polarity pathway regulates convergent extension movements in mammals based on defects in cochlear development and the presence of severe neural tube defects in Dvl1/Dvl2 mutant mice (Wang et al. 2005, Wang et al. 2006). We have recently submitted a manuscript describing the phenotype of Dvl3 mutants (Etheridge et al., submitted). Future experiments will concentrate on the role of the three Dvl genes in regulating the Wnt and PCP pathways during brain development and the effects of mutations in these genes on behaviors such as social interaction.

Autism and Brain Overgrowth
Autism is a devastating disorder first appearing in early childhood in which children display deficits in social behavior and language. The causes are unknown, but based on heritability estimates there is likely to be an important genetic component. Recently, children with autism were found to display increased head circumferences and potentially enlarged brains, but these phenotypes have been difficult to study. As part of an Autism Center of Excellence at UCSD, led by Eric Courchesne, children will be identified who are at risk for autism as early as one year of age. Structural and functional studies of the brains of these children will be performed at one, two and three years of age, when the diagnosis of autism can be confirmed. The imaging studies of the brains of children diagnosed with autism will be compared with controls for evidence of general and regional brain overgrowth. Variations and mutations in genes with expected roles in mitosis, neurogenesis, growth and apoptosis will be determined and correlated with autism and brain overgrowth.