Molecules in focus
Reelin and its complex involvement in brain development and function

https://doi.org/10.1016/j.biocel.2012.06.002Get rights and content

Abstract

Reelin is a neuroprotein with crucial role during neurodevelopment and also in postnatal period. It regulates neuronal migration and positioning in developing neocortex and cerebellar cortex. Postnatally it participates in regulation of dendritic and axonal growth, synaptogenesis, neurotransmission and it contribute to synaptic plasticity necessary for learning and memory functions. Role of Reelin seems to be rather complex, profound research gradually uncovers its further functions. Deficits of Reelin were detected in neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism. Pathogenesis of these disorders is far from being clearly understood. Reelin contribution to these diseases seems to be vital, since genetic variants of Reelin were associated with these diseases and often influence symptom severity. Reelin is a promising candidate molecule with potential future use in diagnostics and therapy, however further detailed research is essential.

Introduction

Reelin (encoded by RELN gene, 7q22) is an extracellular protein involved in regulation of neuronal migration during neurodevelopment and with postnatal roles in maintaining synaptic plasticity, control of neurotransmission as well as regulation of nerve-muscle connectivity (D’Arcangelo et al., 1995, Herz and Chen, 2006, Quattrocchi et al., 2003). Reeler mice, spontaneous genetic variants lacking Reelin gene were firstly described in 1951 (Falconer, 1951). The name reeler came from the typical reeling gait of these mice. Later on neuroanatomical impairments were identified in these mice such as decreased size of the cerebellum lacking foliation pattern and disrupted laminar organisation of cortical layers (D’Arcangelo et al., 1995). These findings explained the typical behavioural characteristics of reeler and contributed to identification of the neurodevelopmental gene altered in these mice. RELN gene location was identified at the early nineties (DeSilva et al., 1997) and the mechanism of its action was also identified. At the beginning of the 21st century, the role of Reelin has been excessively studied and the studies revealed other important roles not restricted on prenatal period but preserved during lifespan.

Section snippets

Structure

DeSilva et al. (1997) mapped RELN gene and identified its position on 7q22 chromosomal region. Reelin protein structure was gradually identified by the end of 20th century (D’Arcangelo et al., 1995). Upon synthesis, Reelin protein is excreted from cytoplasm towards extracellular matrix, where it binds to apolipoprotein receptors at the cell membrane (see below). Reelin is a large glycoprotein of 388 kDa molecular weight it consists of 3461 amino acids. The protein molecule includes signal

Expression, activation and turnover

During prenatal period, Reelin is expressed by Cajal-Retzius neurons, the earliest neurons formed in the marginal zone during brain development. 95% of these neurons degenerate within weeks after birth (Soriano and Del Río, 2005). However, Reelin expression preserves in adulthood. Postnatally Reelin is expressed by a subset of cortical GABA-ergic interneurons, cerebellar granule cells and hippocampal interneurons (Fatemi, 2005, Herz and Chen, 2006).

Reelin provides its functions via proteolytic

Biological function

Reelin function during prenatal brain development has been a focus for decades and thus is well described. As mentioned above, it is expressed prenatally by Cajal-Retzius neurons, the oldest neurons formed near ventricular zone. They migrate a short distance towards marginal zone, where they settle and become a part of pial surface of the developing neocortex (Marín-Padilla, 1998). Later born neurons migrate from ventricular zone towards pial surface. As they reach marginal zone with

Role in diseases

Reelin is a neurodevelopmental molecule with significant postnatal role in modulation of brain functions therefore it is understandable that altered Reelin pathway plays a role in pathogenesis of neurodevelopmental and neuropsychiatric disorders such as schizophrenia, bipolar disorder and autism. Reelin expression is 50% downregulated in psychotic brain, namely in cerebella of schizophrenia and bipolar disorder patients and in frontal cortex and cerebella of autism patients (Fatemi et al., 2001

References (38)

  • S. Baron-Cohen et al.

    Sex differences in the brain: implications for explaining autism

    Science

    (2005)
  • Y. Chen et al.

    Reelin modulates NMDA receptor activity in cortical neurons

    Journal of Neuroscience

    (2005)
  • G. D’Arcangelo et al.

    A protein related to extracellular matrix proteins deleted in the mouse mutant reeler

    Nature

    (1995)
  • U. DeSilva et al.

    The human Reelin gene: isolation, sequencing, and mapping on chromosome 7

    Genome Research

    (1997)
  • P. Absil et al.

    Effects of testosterone on Reelin expression in the brain of male European starlings

    Cell and Tissue Research

    (2003)
  • D.S. Falconer

    Two new mutants, ‘trembler’ and ‘reeler’, with neurological actions in the house mouse (Mus musculus L.)

    Journal of Genetics

    (1951)
  • S.H. Fatemi et al.

    Altered levels of Reelin and its isoforms in schizophrenia and mood disorders

    Neuroreport

    (2001)
  • S.H. Fatemi

    Reelin glycoprotein: structure, biology and roles in health and disease

    Molecular Psychiatry

    (2005)
  • M. Frotscher

    Dual role of Cajal-Retzius cells and reelin in cortical development

    Cell and Tissue Research

    (1997)
  • Cited by (40)

    • Estrogen receptor beta and neural development

      2021, Vitamins and Hormones
      Citation Excerpt :

      Reelin is a large secreted glycoprotein mainly found in the GABAergic interneurons of the post-natal cortex where it participates in synaptogenesis, long-term potentiation, and dendritic outgrowth (Lakatosova & Ostatnikova, 2012). In the developing brain, however, reelin expression is restricted to Cajal-Retzius cells that migrate from the hippocampus and neocortex to the marginal/layer 1 zone of the developing cortex (Lakatosova & Ostatnikova, 2012). In this process, reelin is essential for proper cortical layering by promoting radial glia differentiation, migration, and fiber orientation (Frotscher, 1998; Lakatosova & Ostatnikova, 2012).

    • Serotonin and development

      2020, Handbook of Behavioral Neuroscience
    • Expression of Cntnap2 (Caspr2) in multiple levels of sensory systems

      2016, Molecular and Cellular Neuroscience
      Citation Excerpt :

      In addition, in the cortex, in which many abnormalities have been linked to ASD (Chen et al., 2015), we could detect Caspr2 in all areas examined. During development the dynamic expression of Caspr2 in the cortex and hippocampus is very similar to that of Reelin, a protein that is involved in the regulation of neuronal migration and modulation of synaptic plasticity (Lakatosova and Ostatnikova, 2012). Both Reelin and Caspr2 have previously been linked to ASD (Poot, 2015; Wang et al., 2014).

    View all citing articles on Scopus
    View full text