HeterozygousDab1Null Mutation Disrupts Neocortical and Hippocampal Development

Abstract

AbstractLoss-of-function mutations in Reelin and DAB1 signaling pathways disrupt proper neuronal positioning in the cerebral neocortex and hippocampus, but the underlying molecular mechanisms remain elusive. Here, we report that heterozygousyotarimice harboring a single autosomal recessiveyotarimutation ofDab1exhibited a thinner neocortical layer 1 than wild-type mice on postnatal day (P)7. However, a birth-dating study suggested that this reduction was not caused by failure of neuronal migration.In uteroelectroporation-mediated sparse labeling revealed that the superficial layer neurons of heterozygousyotarimice tended to elongate their apical dendrites within layer 2 than within layer 1. In addition, the CA1 pyramidal cell layer in the caudo-dorsal hippocampus was abnormally split in heterozygousyotarimice, and a birth-dating study revealed that this splitting was caused mainly by migration failure of late-born pyramidal neurons. Adeno-associated virus (AAV)-mediated sparse labeling further showed that many pyramidal cells within the split cell had misoriented apical dendrites. These results suggest that regulation of neuronal migration and positioning by Reelin-DAB1 signaling pathways has unique dependencies onDab1gene dosage in different brain regions.