Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses

Abstract

Over half a century ago, D. S. Falconer first reported a mouse with a reeling gate. Four decades later, the Reln gene was isolated and identified as the cause of the reeler phenotype. Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Reln gene, results in abnormal neuronal layering throughout several regions of the brain. In the years since, the known functions of Reelin signaling in the brain have expanded to include multiple postdevelopmental neuromodulatory roles, revealing an ever increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation of synaptic function. In writing this review, we intend to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromodulatory effects shape and protect synapses.

Physiological significance of proteolytic processing of Reelin revealed by cleavage-resistant Reelin knock-in mice

“…Reelin is known to positively regulate neurogenesis 3,52 , synapse formation 1,7,52,54 , and synaptic plasticity 1,7,52,54 . Whether these events are altered in KI/KI mice is currently being investigated.…”

“…Reelin is a large secreted glycoprotein that regulates many important events in mammalian brain development [1][2][3] . It is also involved in synaptic plasticity and the modulation of higher brain functions 1,[4][5][6][7][8] .…”

“…Reelin is a large secreted glycoprotein that regulates many important events in mammalian brain development [1][2][3] . It is also involved in synaptic plasticity and the modulation of higher brain functions 1,[4][5][6][7][8] . At the cellular level, Reelin induces the clustering of apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which is the prerequisite for the phosphorylation of the cytosolic adaptor protein Dab1 [9][10][11] .…”

“…At the cellular level, Reelin induces the clustering of apolipoprotein E receptor 2 (ApoER2) and very-low-density lipoprotein receptor (VLDLR), which is the prerequisite for the phosphorylation of the cytosolic adaptor protein Dab1 [9][10][11] . Phosphorylated Dab1 is quickly degraded 1,2,5 . Thus, the amount of Dab1 is indicative of the strength of Reelin signaling [12][13][14][15] .…”

“…Thus, the amount of Dab1 is indicative of the strength of Reelin signaling [12][13][14][15] . Several pathways act downstream of Dab1 phosphorylation and regulate the cytoskeleton, adhesion molecules, ion channels, and neurotransmitter release [1][2][3]5,16 . Accordingly, insufficient Reelin signaling could contribute to the pathogenesis of neuropsychiatric disorders, such as epilepsy [17][18][19] , schizophrenia 6,16,20 , and autism 3,8,16 .…”