Abstract
REST (RE1-silencing transcription factor, also called Nrsf) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells in vitro by preventing precocious expression of neuronal genes. REST expression was then decreased in developing neurons to down-regulate neuronal genes which allow their maturation. However, the function of REST during neurogenesis in vivo remains to be elucidated because of the early embryonic lethal phenotype of conventional Rest knockout mice. In order to investigate the role of REST in ocular tissues, we generated and examined the mice evoking genetic ablation to Rest specifically to neural tissues including ocular tissue. We used a Sox1-Cre allele to excise the floxed Rest gene in the early neural tissues including the lens and retinal primordia. The resulting Rest conditional knockout (CKO) and co cntrol mice were used in comparative morphological, histological, and gene expression analyses. Rest CKO mice had an abnormal lens morphology after birth. The proliferation of lens epithelial cells was likely to be slightly reduced, and vacuoles formed without a visible increase in apoptotic cells. Although the aberrant expression of late onset cataract marker proteins was not detected, the expression of Notch signaling-related genes including a previously identified REST-target gene was up-regulated around birth, and this was followed by the down-regulated expression of lens fiber regulators such as c-Maf and Prox1. Rest CKO induces a unique cataract phenotype just after birth. Augmented Notch signaling and the down-regulated expression of lens fiber regulator genes may be responsible for this phenotype. Our results highlight the significance of REST function in lens fiber formation, which is necessary for maintaining an intact lens structure.
Highlights
The transcriptional repressor RE1-silencing transcription factor, REST, was initially discovered as a negative regulator of neuron-specific genes in non-neuronal cells [1,2]
The REST repressor complex has been shown to regulate the differentiation of neuronal progenitors to mature neurons, during which the gradual loss of REST repressor complex binding with the target RE1 site ensures the up-regulated expression of target neuronal genes [7]
The embryonic lethal nature of Rest gene knockout mice has hampered investigations on the roles of REST in the late developmental stage, we generated Rest conditional knockout (CKO) mice and demonstrated that Rest played a role in the differentiation and maturation of lens fiber cells
Summary
The transcriptional repressor RE1-silencing transcription factor, REST ( known as neuronrestrictive silencer factor NRSF), was initially discovered as a negative regulator of neuron-specific genes in non-neuronal cells [1,2]. Rest and Lens Differentiation represses the expression of neuronal genes by transcriptionally silencing their promoters in conjunction with CoREST [3]. Previous studies have shown that the expression of Rest is down-regulated as neural stem cells (NSCs) differentiate into mature neurons, and is completely silenced in mature adult neurons [7]. The repressor function of REST indicates that it plays a central role in inhibiting the precocious expression of neuronal genes in NSCs. its down-regulation upon the receipt of neuronal differentiation cues has been shown to permit the robust expression of neuronal genes for terminal differentiation [7]
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