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DAB2IP regulates neuronal migration and neurite development in the developing neocortex
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Lee, Gum Hwa. DAB2IP regulates neuronal migration and neurite development in the developing neocortex. Retrieved from https://doi.org/doi:10.7282/T3FN1504

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TitleDAB2IP regulates neuronal migration and neurite development in the developing neocortex
NameLee, Gum Hwa (author); Firestein, Bonnie (chair); D'Arcangelo, Gabriella (internal member); Hsu, Shu Chan (internal member); Rasin, Mladen-Roko (outside member); Rutgers University; Graduate School - New Brunswick
Date Created2012
Other Date2012-10 (degree)
SubjectCell and Developmental Biology, Neurons--Physiology, Cerebral cortex, Nerve tissue proteins, Proteins
Extentx, 112 p. : ill.
DescriptionDab2ip (DOC-2/DAB2 interacting protein) is a member of the Ras GTPase-activating protein (GAP) family that has been previously shown to function as a tumor suppressor in several systems. Dab2ip is also highly expressed in the brain where it interacts with Dab1, a key mediator of the Reelin pathway that controls several aspects of brain development and function. I found that Dab2ip is highly expressed in the developing cerebral cortex, but that mutations in the Reelin signaling pathway do not affect its expression. To determine whether Dab2ip plays a role in brain development, I knocked down or over expressed it in neuronal progenitor cells of the embryonic mouse neocortex using the in utero electroporation technique. Dab2ip down-regulation severely disrupts neuronal migration, affecting preferentially late-born principal cortical neurons. Dab2ip overexpression also leads to migration defects. Structure-function experiments in vivo further show that both PH and GRD domains of Dab2ip are important for neuronal migration. A detailed analysis of transfected neurons reveals that Dab2ip down- or up-regulation disrupts the transition from a multipolar to a bipolar neuronal morphology in the intermediate zone. Knock down of Dab2ip in neurons ex-vivo indicates that this protein is necessary for proper neurite development and for the expression of several major neuronal microtubule associated proteins (MAPs), which are important for neurite growth and stabilization. To further investigate the role of Dab2ip in the developing brain, I also conducted Western blot analysis of brain lysates obtained from Dab2ip knockout mice. I found that Dab2ip deficiency results in the abnormal activity of signal transduction pathways involving the Erk1/2 and Akt kinases during early embryonic brain development, and confirmed that Dab2ip is necessary for the expression of MAPs. Furthermore, I discovered that Dab2ip is required for maintaining the normal levels of Dab1 specifically during embryonic, but not postnatal, brain development. Thus, this study identifies, for the first time, a critical role for Dab2ip in mammalian cortical development and begins to reveal molecular mechanisms that underlie this function.
NotePh.D.
NoteIncludes bibliographical references
Noteby Gum Hwa Lee
Genretheses, ETD doctoral
Persistent URLhttps://doi.org/doi:10.7282/T3FN1504
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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