Malformations of cortical development due to disorder of neuronal migration are increasingly recognized as a common cause of epilepsy, mental retardation, and cerebral palsy. The doublecortin (DCX) gene is critical for neuronal migration in humans, as mutations result in X- linked lissencephaly in males and double cortex in females, producing severe neurocognitive deficits. We identified the DCX gene and found mutations in patients with this condition. We identified its role as a microtubule-associated protein (MAP) and its involvement in critical signaling pathways through phosphorylation- and dephosphorylation-dependent mechanisms. We uncovered important cellular roles for Dcx in cells, including mediation of nuclear-centrosome coupling, organization of microtubule condensation at the neurite "wrist" and a requirement in adult stem cell migration. Dcx is part of a gene family also containing Dclk1 and Dclk2, each encoding a strongly brain-expressed protein with a closely matching Dcx domain and kinase domain. We found that Dcx;Dclk1 knockouts displays severe cortical neuronal migration defects that mirror lissencephaly, whereas Dcx;Dclk2 knockouts displays severe seizures, also part of the clinical picture of lissencephaly. However, the role of the kinase activities in neuronal development are unknown. The overall goal of this renewal application is to elucidate the signaling mechanisms of the Dcx gene family in neuronal development and brain function. We will utilize knockout and knock-in and genetic rescue experiments in mice combined with advanced live-cell imaging capabilities and in vivo analysis that will synergize to provide a powerful approach to address these goals.

Public Health Relevance

The doublecortin gene family plays critical roles in brain development, resulting in severe forms of epilepsy and mental retardation when mutated. We will study the signaling mechanisms of the doublecortin gene family, in order to understand the basis of these human diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Riddle, Robert D
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Novarino, Gaia; Fenstermaker, Ali G; Zaki, Maha S et al. (2014) Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. Science 343:506-11
Baek, Seung Tae; Kerjan, Geraldine; Bielas, Stephanie L et al. (2014) Off-target effect of doublecortin family shRNA on neuronal migration associated with endogenous microRNA dysregulation. Neuron 82:1255-62
Akizu, Naiara; Silhavy, Jennifer L; Rosti, Rasim Ozgur et al. (2014) Mutations in CSPP1 lead to classical Joubert syndrome. Am J Hum Genet 94:80-6
Shin, Euikyung; Kashiwagi, Yutaro; Kuriu, Toshihiko et al. (2013) Doublecortin-like kinase enhances dendritic remodelling and negatively regulates synapse maturation. Nat Commun 4:1440
Paciorkowski, Alex R; Keppler-Noreuil, Kim; Robinson, Luther et al. (2013) Deletion 16p13.11 uncovers NDE1 mutations on the non-deleted homolog and extends the spectrum of severe microcephaly to include fetal brain disruption. Am J Med Genet A 161A:1523-30
Abdel Aleem, Alice; Abu-Shahba, Nourhan; Swistun, Dominika et al. (2011) Expanding the clinical spectrum of SPG11 gene mutations in recessive hereditary spastic paraplegia with thin corpus callosum. Eur J Med Genet 54:82-5
Novarino, Gaia; Akizu, Naiara; Gleeson, Joseph G (2011) Modeling human disease in humans: the ciliopathies. Cell 147:70-9
Diaz, Alejandro L; Gleeson, Joseph G (2009) The molecular and genetic mechanisms of neocortex development. Clin Perinatol 36:503-12
Kerjan, Geraldine; Gleeson, Joseph G (2009) Moving neurons back into place. Nat Med 15:17-8
Bielas, Stephanie L; Serneo, Finley F; Chechlacz, Magdalena et al. (2007) Spinophilin facilitates dephosphorylation of doublecortin by PP1 to mediate microtubule bundling at the axonal wrist. Cell 129:579-91

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