Proper cerebral cortical development depends on the tightly orchestrated migration of newly born neurons from the inner ventricular and subventricular zones to the outer cortical plate. Any disturbance in this process during prenatal stages may lead to neuronal migration disorders (NMDs), which the NIH estimates may result in more than 25 described syndromes including childhood epilepsy and cerebral palsy. The problem is exacerbated by the very limited means at our disposal to ameliorate these illnesses, which makes it even more important to untangle the complex molecular and cellular processes that are active during neuronal migration and the dysregulation of which may underlie NMDs. Our previous work demonstrated focal neuronal migration defects in mice carrying loss-of-function alleles of the recognized autism risk gene Wdfy3. Our proposed experiments aim to untangle the cellular origins of these defects by using mosaic analysis with double markers, a powerful genetic labeling tool to track cells with respect to genotype and time of birth. In addition, we will examine morphology and synaptic density of homozygous mutant and wild type neurons in MADM reporter mice in an otherwise heterozygous tissue context to uncover the consequences Wdfy3 loss has on cellular function and interconnectivity. In summary, our proposal will provide a detailed outline of Wdfy3 function in neuronal migration by enabling the direct comparison of Wdfy3 mutant and wild type neurons with respect to proper migratory behavior and morphology.
Neuronal migration disorders are often severe brain defects of poorly understood etiology that manifest during prenatal development. Our research will uncover how a key molecule causative in autism and neuronal migration disorders regulates proper migration of young neurons in the cerebral cortex.
