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Pathways Reelin Signaling Pathway
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Submitted by:  Michael Shih, PhDEmail Michael Shih, PhD Guru: Email

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Description: Description: Reelin is an extracellular protein secreted by neurons. Reeler mice with a defective Reelin gene exhibit neuronal abnormalities in development. Mice that are heterozygous for the Reelin knockout have neuroanatomical and behavioral traits similar to those of schizophrenia patients, suggesting that mice with a deficiency in Reelin may provide a useful model for schizophrenia. Reelin protein may be involved in cognitive function in adults as well as playing a role in the developmental organization of neurons in the cortex. Multiple cell surface receptors transduce Reelin signaling into neurons. One class of Reelin receptor includes the VLDL receptor and the ApoER2. The intracellular adaptor Dab1 binds to the VLDL receptor and ApoER2 receptor through an NPxY motif and is involved in transmission of Reelin signals through these lipoprotein receptors. Mutation of the mDab1 gene in mice creates a phenotype identical to Reeler mice, supporting the role of this cytoplasmic factor in signaling downstream from Reelin. Another class of receptor for Reelin is the cadherin-related neuronal receptors, CNR receptors. Reelin signaling through several different CNR receptors activates the Fyn tyrosine kinases. Reelin stimulates phosphorylation of Dab1 and Dab1 appears to link Reelin signaling with tyrosine kinases. Disruption of the p35 and Cdk5 genes in mice indicates that cdk5 is also involved in the role of Reelin in neuronal development.
Description: Description: Glenn Croston, PhD
Description: Description:
references: references: Ballmaier, M., Zoli, M., Leo, G., Agnati, L.F., Spano, P. (2002) Preferential alterations in the mesolimbic dopamine pathway of heterozygous reeler mice: an emerging animal-based model of schizophrenia. Eur. J. Neurosci. 15(7), 1197-1205

Fatemi, S.H., Kroll, J.L., Stary, J.M. (2001) Altered levels of Reelin and its isoforms in schizophrenia and mood disorders. Neuroreport. 12(15), 3209-15

Hong, S.E. et al. (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat. Genet. 26(1), 93-6

Howell, B.W. et al. (2000) Dab1 tyrosine phosphorylation sites relay positional signals during mouse brain development. Curr. Biol. 10(15), 877-85

Howell, B.W., Gertler, F.B., Cooper, JA. (1997) Mouse disabled (mDab1): a Src binding protein implicated in neuronal development. EMBO J. 16(1), 121-32

Ohshima, T. et al.(2001) Synergistic contributions of cyclin-dependant kinase 5/p35 and Reelin/Dab1 to the positioning of cortical neurons in the developing mouse brain. Proc Natl Acad Sci U S A 98(5):2764-9

Rice, D.S. et al. (1998) Disabled-1 acts downstream of Reelin in a signaling pathway that controls laminar organization in the mammalian brain. Development 125(18), 3719-29

Senzaki, K., Ogawa, M., Yagi, T. (1999) Proteins of the CNR family are multiple receptors for Reelin. Cell 99(6), 635-47

Smith D., Tsai L. Cdk5 behind the wheel: a role in trafficking and transport? Trends in Cell Biology 2002 Vol 12(1): pp 28-36

Trommsdorff, M. et al. (1999) Reeler/Disabled-like disruption of neuronal migration in knockout micelacking the VLDL receptor and ApoE receptor 2. Cell 97(6), 689-701



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