Novel Rest functions revealed by conditional gene ablation
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Rest is a regulator of neuronal development and has been suggested to function in maintaining the pluripotent state of embryonic stem cells (ESCs); however, this remains controversial. Since Rest null mice show embryonic lethality, we herein generated conditional Rest knockout (CKO) models to investigate Rest functions in more detail. Our results revealed that Rest was not necessary for maintaining the pluripotency of ESCs and instead promoted primitive endoderm differentiation. In contrast to the repressive role of Rest in vitro, including ESCs, neural stem cells, and fibroblasts, on the expression of target neural genes, Rest CKO did not affect the in vivo development of brain tissue. However, the same Rest CKO mice showed an abnormal lens morphology after birth with augmented Notch signaling and down-regulated lens fiber regulator gene expression. The ablation of Rest during neural crest cell (NCC) development caused neonatal lethality due to swelling of the digestive tract with reductions in acetylcholinesterase activity in the myenteric plexus derived from NCCs. Furthermore, a reduced number of melanocyte precursors also derived from NCCs resulted in white spotted coat color phenotypes lacking mature melanocytes. Rest controls thousands of target genes and may have many unknown functions related to diseases.
KeywordsRest/Nrsf Neural differentiation Conditional gene ablation Neural crest cell Neural stem cell Vagus nerve
We thank Drs. Yasuhiro Yamada and Takahiro Kunisada for their thoughtful advice. This research was funded by a Grant from Gifu University Graduate School of Medicine and a Grant supported by Gifu University KASSEIKA-KEIHI (24KW). This investigation was supported in part by the Mochida Memorial Foundation for Medical and Pharmaceutical Research (H27 KEN 2-1).
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
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