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Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly

Molecular Psychiatry volume 6, pages 129–133 (2001)Cite this article

A number of recent reports implicate the Reelin glycoprotein in the etiology of several neurodevelopmental disorders ie, schizophrenia,123 bipolar disorder,23 major depression,2 lissencephaly4 and autism.56566 Moreover, converging data point to Reelin as an important modulator of a neuronal signaling system that may be involved in synaptic transmission and plasticity.6 I will discuss the various lines of evidence clarifying the role of Reelin in brain development and cell signaling and in the genesis of several brain disorders.

Reeler is an autosomal recessive mutant mouse that was first discovered nearly 50 years ago.7 This mutation produced an ataxic and reeling gait in the affected mice. Analysis of the central nervous system in the mutant mouse revealed multiple defects such as inverted cortical lamination, abnormal positioning of neurons and aberrant orientation of cell bodies and fibers.78 In the cerebral cortex of the reeler mouse, neurons destined to form the subplate zone occupy ectopic positions in superficial cortical layers. Additionally, neurons developed later which are destined to form the cortical plate, fail to bypass previously generated neurons.8 Thus, an inverted pattern of cortical development takes place in the mutant mice. Moreover, profound cerebellar hypoplasia is evident in brains of reeler-mutant mice.91011 Reelin RNA is first detectable in the mouse embryonic brain on day 9.5.12 It then increases in concentration up to early postnatal days and then declines to adult levels. The first cells producing Reelin are the Cajal–Retzius neurons which begin differentiation as early as day 9.5 in the embryonic mouse brain;13 these are transient neurons that act as pathfinders and help in the early laminar organization of the cortex.1314 In the adult mammalian brain, Reelin is localized to layer I cortical Cajal–Rezius cells, cortical GABAergic interneurons in layers II through VI,115 cerebellar granular cells16 and hippocampal interneurons.2 Reelin is also present in a number of embryonic sites such as embryonic spinal cord,17 subpial granular layer of fetal human cortex18 and developing rat striatum.19

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Acknowledgements

The author's work is supported by grants from Stanley Foundation, National Alliance for Research in Affective Disorders and Schizophrenia, Minnesota Medical Foundation and Kunin Fund of St Paul Foundation. SH Fatemi is an established Phyllis and Perry Schwartz NARSAD investigator. The secretarial help of Ms Janet Holland is appreciated.

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  1. Department of Psychiatry, Division of Neuroscience Research, University of Minnesota Medical School, Minneapolis, 55455, MN, USA

    S H Fatemi

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Fatemi, S. Reelin mutations in mouse and man: from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly. Mol Psychiatry 6, 129–133 (2001). https://doi.org/10.1038/sj.mp.4000129

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