White spotting phenotype induced by targeted REST disruption during neural crest specification to a melanocyte cell lineage

Aoki, Hitomi; Hara, Akira; Kunisada, Takahiro

doi:10.1111/gtc.12235

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…The embryonic lethal nature of Rest gene knockout mice has hampered investigations on Rest function in the later developmental stage. To overcome this, we generated various types of Rest CKO mice and demonstrated that Rest plays a role in the differentiation and maturation of various cell types (Aoki, 2018; Aoki et al., 2012, 2014, 2015, 2016; Yamada et al., 2010). As previously described by using the Sox1‐Cre; Rest floxed/floxed mice, the genetic ablation of Rest in the whole brain in vivo does not result in altered expression of target genes and the mice lacking Rest in the brain are apparently normal and grow into adults (Aoki et al., 2012); however, the Sox1‐Cre; Rest floxed/floxed mice induces a unique cataract phenotype just after birth and developed severe lens opacity in adulthood without any morphological malformation in other ocular tissues with the up‐regulated expression of Notch signaling‐related genes including a previously identified REST‐target gene around birth followed by the down‐regulated expression of lens fiber regulators such as c‐Maf and Prox1 (Aoki et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Induced genetic ablation of Rest leads to the alteration of stimulus‐induced response of the vagal nerve

et al. 2021

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Rest (RE1‐silencing transcription factor, also called Nrsf) is involved in the maintenance of the undifferentiated state of neuronal stem/progenitor cells by preventing precocious expression of neuronal genes. In order to further investigate the function of Rest in neurons, we generated and examined mice evoking genetic ablation of Rest specifically in neural tissues by generating Rest conditional knockout mice. As the Rest knockout mice are embryonically lethal, we used a Sox1‐Cre allele to excise the floxed Rest gene from the early stage of nerve cell differentiation including neural crest‐derived nerve cells. Using this conditional Rest knockout Sox1‐Cre; Restflox/flox mice, we have revealed the role of Rest in the parasympathetic nervous system in the stomach and heart

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Section: Discussionmentioning

confidence: 99%

Induced genetic ablation of Rest leads to the alteration of stimulus‐induced response of the vagal nerve

et al. 2021

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“…We observed the expanded berry white spots in viable heterozygous NC cell-specific Rest CKO mice Single Cell Biology Aoki [21]. This white spotting phenotype was associated with the reduction in the number of melanocytes in the embryonic skin.…”

Section: Commentarymentioning

confidence: 79%

Rest as a New Transcription Factor to Control Neural Crest Development

Aoki¹,

Kunisada²

2016

Single Cell Biol

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RE1-silencing transcription factor (Rest), also known as NRSF (neuro-restrictive silencer factor), is a negative regulator of neuron-specific genes and expressed during embryonic development to prevent neural gene expression in non-neuronal cells. However, Rest null mice die by E11.5, prior to which the growth retardation caused by widespread apoptotic cell death has precluded further analyses of the potential role of Rest in vivo. In order to investigate the function of Rest in neural crest cells (NCCs) which are known to differentiate into neuronal and nonneuronal lineages, we established NCC-specific homozygous Rest conditional knockout (CKO) mice and observed their neonatal death caused by the defect of enteric nerve cells derived from NCCs. The viable heterozygous NCCspecific Rest CKO mice showed the white spotting phenotype, associated with a reduction in the number of melanoblasts, a non-neuronal derivative of NCCs, in embryonic skin. These results suggest the expression of REST during the early NCC specification stage is necessary for the proper development of NCCs. To fully understand the mechanisms of white spot formation and postnatal death or embryonic lethality mediated by the Rest ablation, future experiments should focus on single cell analysis to characterize the detailed cellular events such as reduced cell cycle, apoptosis, change of the cell fate to well explain the observed phenotypic changes. Keywords: Rest/NRSF; Neural crest cells; Melanocytes; Conditional knockout mouse CommentaryRE1-silencing transcription factor (REST), also known as NRSF (neuron-restrictive silencer factor), is a zinc finger protein that binds to a conserved 23 bp motif known as RE1 (repressor element, also called NRSE) found in more than 1000 of genes determining the fundamental neuronal traits [1,2]. Rest is working in undifferentiated stem cells as well as during neural maturation [3][4][5]. During embryonic stem cell (ESC) differentiation, Rest expression is highest in undifferentiated ESCs and is down-regulated as the ESCs differentiate into neuronal stem cells (NSCs) then completely silenced in mature neuronal cells [6].Unfortunately, Rest KO mice showed embryonic lethality and these observations have been tested only by in vitro culture system. To investigate the Rest function in vivo, Rest conditional knockout (CKO) mice carrying the floxed last exon of Rest encoding the coRest binding site, essential for the construction of Rest silencing complex was developed [7,8].By using this conditional knockout (CKO) system, Rest was shown to promote the early differentiation of ESCs by silencing Nanog expression during the early differentiation of ESCs in vitro. Nanog is a member of core transcription factor in the maintenance of ESC pluripotency and harbors RE site in its promoter. It was also shown that Rest is not required for the maintenance of undifferentiated state of ESCs [9]. Then Rest was shown to play a role in suppressing the expression of neuronal genes in cultured neuronal cells. Surprisingly, by usi...

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“…As the REST-CoREST complex specifically regulates repression of differentiation-associated genes during neural development (12), it is not wholly surprising that this complex would be reactivated to dictate the differentiation/proliferation balance in human melanoma cells. Indeed, expression of REST, the binding partner for CoREST, has been shown to be critical for early neural crest specification of developing melanoblasts (42), a phenotype that resembles the cell lines using the Broad Institute's DepMap portal (https://depmap.org/portal/) found statistically significant inverse dependencies of expression of MITF with SNAI1 and AXL with SNAI2 as well as a significant inverse relationship between SNAI1 and of critical EMT-like embryonic and wound-healing transcriptional programs as well as cellular responses to environmental stressors, as seen in phenotypic reprogramming of cancer cells exposed to pharmacologic therapies (50). Indeed, a survey of melanoma endocrine therapies in estrogen receptor-positive (ER + ) breast cancers and associated tumor cell plasticity (17).…”

Section: Discussionmentioning

confidence: 99%

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma

Wu,

Hanly,

Gibson

et al. 2024

Journal of Clinical Investigation

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White spotting phenotype induced by targeted REST disruption during neural crest specification to a melanocyte cell lineage

Cited by 8 publications

References 36 publications

Induced genetic ablation of Rest leads to the alteration of stimulus‐induced response of the vagal nerve

Induced genetic ablation of Rest leads to the alteration of stimulus‐induced response of the vagal nerve

Rest as a New Transcription Factor to Control Neural Crest Development

The CoREST repressor complex mediates phenotype switching and therapy resistance in melanoma

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