Functional Role of SIL1 in Neurodevelopment and Learning

Abstract

Background. Sil1 is the causative gene of Marinesco-Sjӧgren Syndrome (MSS). The mutated Sil1 generates shortened SIL1 protein which will form aggregation and be degraded rapidly. Mental retardation is a major symptom of MSS which suggests a role of SIL1 in the development of the central nervous system, but how SIL1 functions remains unclear. Objectives. The aim of this study is to explore the role of SIL1 in regulating cerebral development and its underlying molecular mechanism. Methods. The basic expression pattern of SIL1 in tissues and cultured cortical neurons is measured by immunostaining and Western blot. The expression of SIL1 is reduced in vitro and in vivo through RNA interference delivered by a lentivirus. The expression of NMDA receptor subunits and the function of the Reelin signaling pathway are then examined by surface biotinylation and Western blot subsequently. Finally, the spatial learning of young mice was assessed by the Barnes maze task. Results. SIL1 deficiency caused a diminished expression of both Reelin receptors and therefore impaired the Reelin signaling pathway. It then inhibited the developmental expression of GluN2A and impaired the spatial learning of 5-week-old mice. Conclusions. These results suggested that SIL1 is required for the development of the central nervous system which is associated with its role in Reelin signaling.

Reelin functions beyond neuronal migration: from synaptogenesis to network activity modulation

“…Finally, accordingly with previous and more recent studies 55,[56][57][58] , the contribution of Reelin signaling to the genetic and behavioral expression of learning and memory has been confirmed 59,60 . Indeed, an interesting work using epigenomic analysis revealed that the binding of Reelin to its receptor results in the expressions of immediate early genes involved in synaptic plasticity, and that these epigenomic changes possibly involve nuclear translocation of the intracellular domain of ApoER2 61 .…”

SIL1 improves cognitive impairment in APP23/PS45 mice by regulating amyloid precursor protein processing and Aβ generation

“…Studies have shown that SIL1 is highly expressed in the hippocampus and is closely associated with neurodevelopment, memory, and learning (Inaguma et al, 2014;Xu et al, 2019). Moreover, SIL1 plays a protective role against AD.…”

“…A previous study showed that SIL1 mainly accumulated in the PSD fraction of neurons and directly interacted with PSD, like GluN2A. Moreover, the SIL1 knockdown resulted in the inactivation of Reelin signaling and obstructed synaptic NMDA receptor maturation in young mice at the age of 3 weeks(Xu et al, 2019).…”

“…The loss-of-function mutation of SIL1 attenuates the interplay between SIL1 and Bip, leading to abnormal cortical development, which is considered an important cause of mental retardation in MSS (Inaguma et al, 2014). SIL1 may also play a role in neurodevelopment and learning independent of its interaction with Bip (Labisch et al, 2018;Xu et al, 2019).…”

Reelin Regulates Developmental Desynchronization Transition of Neocortical Network Activity

“…It has been shown that in the absence of reelin, experience-dependent plasticity in the visual cortex into adulthood was prolonged [40]. The confirmation of the contribution of reelin signaling to the genetic and behavioral expression of learning and memory has been documented [41,42]. Moreover, an epigenomic analysis has revealed that the binding of reelin to its receptor results in the expression of certain immediate early genes involved in synaptic plasticity [43].…”