Emerging topics in Reelin function

Abstract

Reelin signalling in the early developing cortex regulates radial migration of cortical neurons. Later in development, Reelin promotes maturation of dendrites and dendritic spines. Finally, in the mature brain, it is involved in modulating synaptic function. In recent years, efforts to identify downstream signalling events induced by binding of Reelin to lipoprotein receptors led to the characterization of novel components of the Reelin signalling cascade. In the present review, we first address distinct functions of the Reelin receptors Apoer2 and Vldlr in cortical layer formation, followed by a discussion on the recently identified downstream effector molecule n-cofilin, involved in regulating actin cytoskeletal dynamics required for coordinated neuronal migration. Next, we discuss possible functions of the recently identified Reelin-Notch signalling crosstalk, and new aspects of the role of Reelin in the formation of the dentate radial glial scaffold. Finally, progress in characterizing the function of Reelin in modulating synaptic function in the adult brain is summarized. The present review has been inspired by a session entitled 'Functions of Reelin in the developing and adult hippocampus', held at the Spring Hippocampal Research Conference in Verona/Italy, June 2009.

Figure 1. Reelin receptors Apoer2 and Vldlr differentially regulate positioning of radially migrating neurons

Neurons were immunostained for the neuronal marker NeuN in coronal brain sections. In layer I of wildtype (A) and of Apoer2 deficient mice (C) only few NeuN positive cells are detected. In contrast, numerous NeuN-positive cells were found to invade layer I of Vldlr deficient mice (B). Graphical representations A´-C´ illustrate radial migration underlying neuronal positioning in the developing embryonic cortex corresponding to the immunostained sections in A–C. In each pictogram a neuron (N, orange) is shown that migrates from its site of birth in the ventricular zone (vz) along the process of a radial glial cell (RG, blue) towards the marginal zone (mz), future layer I. Reelin is secreted by Cajal-Retzius cells (CR, green) in the marginal zone. In wildtype (A´), migrating neurons do not invade the mz. In Vldlr deficient mice (B´), neurons migrate into the marginal zone. In mice lacking Apoer2 (C´), neurons stop below the marginal zone, similar as in wildtype. Bar: 80 µm

Fig. 2. A model of the complex interplay between Reelin, Apolipoprotein E receptors and amyloid precursor protein at the postsynaptic membrane

Binding of Reelin to its receptors Apoer2 and Vldlr induces Src family kinase Fyn-mediated tyrosine phosphorylation of the neuronal adapter protein Disabled-1, which in turn activates Fyn. The interaction of Reelin and its receptors can be modulated by Apolipoprotein E in an ApoE-isoform dependent manner. In addition to Apoer2 and Vldlr, Reelin also binds to the amyloid precursor protein, APP, which affects its trafficking and proteolytic processing by γ-secretase in a Dab1-dependent manner. In addition, Dab1 might modulate the nuclear trafficking and/or degradation of liberated intracellular domains of γ-secretase substrates, including Notch (not shown here). Intramembrane cleavage of the product of β-secretase-mediated APP processing by γ-secretase results in the extracellular release of neurotoxic amyloid-beta peptide (Aβ). It forms the main constituent of insoluble amyloid plaques, which can contain fragments of Reelin and ApoE as well. In contrast, ectodomain shedding by α-secretase releases the neuroprotective soluble extracellular domain of APP and prevents generation of Aβ. Reelin-dependent activation of Fyn promotes tyrosine phosphorylation of the NMDA receptor subunit NR2 and thereby counteracts Aβ-induced downregulation of synaptic transmission. Oligomeric Aβhigh-affinity binding to the cellular form of prion protein (PrP^C) inhibits LTP (Lauren et al. 2009) and might interfere with the interaction of Aβ with other co-receptors. Aβ binding to one of these coreceptors (possibly nicotinic acetylcholine receptor) activates calcineurin (Calna), which in turn activates striatal enriched phosphatase (Step) by dephosphorylation. Step-mediated NR2 dephosphorylation leads to increased endocytosis, reduced density of NMDA receptors and decreased glutamatergic transmission at the synapse.