Harnessing the master transcriptional repressor REST to reciprocally regulate neurogenesis

Abstract

Neurogenesis begins in embryonic development and continues at a reduced rate into adulthood in vertebrate species, yet the signaling cascades regulating this process remain poorly understood. Plasma membrane-initiated signaling cascades regulate neurogenesis via downstream pathways including components of the transcriptional machinery. A nuclear factor that temporally regulates neurogenesis by repressing neuronal differentiation is the repressor element 1 (RE1) silencing transcription (REST) factor. We have recently discovered a regulatory site on REST that serves as a molecular switch for neuronal differentiation. Specifically, C-terminal domain small phosphatase 1, CTDSP1, present in non-neuronal cells, maintains REST activity by dephosphorylating this site. Reciprocally, extracellular signal-regulated kinase, ERK, activated by growth factor signaling in neural progenitors, and peptidylprolyl cis/trans isomerase Pin1, decrease REST activity through phosphorylation-dependent degradation. Our findings further resolve the mechanism for temporal regulation of REST and terminal neuronal differentiation. They also provide new potential therapeutic targets to enhance neuronal regeneration after injury.

Keywords: CTDSP1; EGF; ERK; Pin1; RE1 silencing transcription factor; REST; astrocyte; brain injury; neuronal differentiation; βTrCP.

Figure 1.

A model for reciprocal regulation of REST through post-translational modifications on serines 861 and 864. In stem cells, REST sits on the chromatin and represses neuronal gene expression (left panel). Here, REST is protected from degradation, because CTDSP1 dephosphorylates serines 861 and 864 on REST. During neuronal differentiation, growth factor signaling (e.g., EGF) increases activation of H-Ras and ERK, resulting in phosphorylation of serines 861 and 864. Pin1 binds to phosphorylated REST, and recruits βTrCP binding as well. βTrCP binding leads to REST degradation, allowing for expression of neuronal genes (right panel).