Information from the study of naturally-occurring mutations in the mouse has made significant contributions to our understanding of mammalian development. The reeler mouse is an ataxic neurodevelopmental mutant that has a defect in cell migration resulting in extensive disruption of laminar structures in the brain. Aberrant laminar organization is apparent in the cerebral cortex, hippocampus and cerebellum and additional defects are seen in several other brain regions including the olivary nucleus and the olfactory bulb. Anatomical and physiological studies of reeler suggest that the mutation affects the ability of postmitotic neurons to assume correct positions in the developing brain. We isolated the gene responsible for the reeler mutation (reelin) by taking advantage of an insertional mutagenesis event. Its protein product has features of extracellular matrix components and it is expressed in a temporal and spatial pattern during embryonic and postnatal development that is consistent with the phenotypic defects observed in reeler mice. Our preliminary results suggest that Reelin is an instructive, extrinsic factor that is required for the cytoarchitectonic organization of the brain and we propose that Reelin functions by interacting with several other extracellular and/or cell surface proteins. We now intend to investigate the function and regulation of expression of Reelin to understand its role in the molecular and cellular events that control mammalian neurodevelopment. As a first step in this analysis, we will prepare expression vectors and antibodies specific for Reelin. These reagents will be used to compare the adhesion and cell migration properties of full length and mutated Reelin in cell culture, brain explants and brain slice preparations. The functional domains of Reelin, defined in these assays, will be used to identify Reelin binding proteins using biochemical approaches as well as the yeast two hybrid system. Genes encoding Reelin binding proteins will be isolated and characterized in terms of their molecular and biological properties. In addition, the reelin promoter will be defined in transgenic mouse studies and used to express mutated Reelin proteins in vivo. This will establish the functional contribution of specific domains of Reelin in a natural context. This proposal will illuminate the cellular and biochemical events involved in cell migration that lead to normal brain development. This knowledge will contribute to an understanding of several pathological conditions, including pediatric epilepsy and schizophrenia. Furthermore, elucidation of the mechanisms responsible for cell migration is critical for the control of tumor invasion and metastasis, particularly in the brain.
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| Dellovade, Tammy; Romer, Justyna T; Curran, Tom et al. (2006) The hedgehog pathway and neurological disorders. Annu Rev Neurosci 29:539-63 |
| Romer, Justyna T; Kimura, Hiromichi; Magdaleno, Susan et al. (2004) Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice. Cancer Cell 6:229-40 |
| Huang, Yongcheng; Magdaleno, Susan; Hopkins, Rachel et al. (2004) Tyrosine phosphorylated Disabled 1 recruits Crk family adapter proteins. Biochem Biophys Res Commun 318:204-12 |
| Yip, Yee Ping; Capriotti, Christine; Magdaleno, Susan et al. (2004) Components of the reelin signaling pathway are expressed in the spinal cord. J Comp Neurol 470:210-9 |
| Homayouni, Ramin; Magdaleno, Susan; Keshvara, Lakhu et al. (2003) Interaction of Disabled-1 and the GTPase activating protein Dab2IP in mouse brain. Brain Res Mol Brain Res 115:121-9 |
| Li, Leyi; Connelly, Michele C; Wetmore, Cynthia et al. (2003) Mouse embryos cloned from brain tumors. Cancer Res 63:2733-6 |
| Andersen, Olav M; Benhayon, David; Curran, Tom et al. (2003) Differential binding of ligands to the apolipoprotein E receptor 2. Biochemistry 42:9355-64 |
| Benhayon, David; Magdaleno, Susan; Curran, Tom (2003) Binding of purified Reelin to ApoER2 and VLDLR mediates tyrosine phosphorylation of Disabled-1. Brain Res Mol Brain Res 112:33-45 |
| Keshvara, Lakhu; Magdaleno, Susan; Benhayon, David et al. (2002) Cyclin-dependent kinase 5 phosphorylates disabled 1 independently of Reelin signaling. J Neurosci 22:4869-77 |
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