Identification of a novel nonsense mutation on the Pax3 gene in ENU-derived white belly spotting mice and its genetic interaction with c-Kit

Guo, Xiao; Ruan, Hai Bin; Li, Yan; Gao, Xiang; Li, Wei

doi:10.1111/j.1755-148x.2010.00677.x

Cited by 14 publications

(22 citation statements)

References 53 publications

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“…Additional experiments demonstrated that signaling via the Kit receptor modulates Mitf and is required for Mitf-dependent induction of Tyrosinase ( Tyr ), a rate limiting enzyme in melanin production (Hou et al, 2000). The study of double heterozygous pigmentation mutants has also revealed the presence of synergistic interactions resulting from underlying molecular interactions between Mitf and the anti-apoptotic factor Bcl2 (McGill et al, 2002) and between the transcription factors Pax3 and Kit (Guo et al, 2010)…”

Section: Discussionmentioning

confidence: 99%

The transcription factors Ets1 and Sox10 interact during murine melanocyte development

Saldana-Caboverde

Perera

Watkins‐Chow

et al. 2015

Developmental Biology

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Melanocytes, the pigment-producing cells, arise from multipotent neural crest (NC) cells during embryogenesis. Many genes required for melanocyte development were identified using mouse pigmentation mutants. The variable spotting mouse pigmentation mutant arose spontaneously at the Jackson Laboratory. We identified a G-to-A nucleotide transition in exon 3 of the Ets1 gene in variable spotting, which results in a missense G102E mutation. Homozygous variable spotting mice exhibit sporadic white spotting. Similarly, mice carrying a targeted deletion of Ets1 exhibit hypopigmentation; nevertheless, the function of Ets1 in melanocyte development is unknown. The transcription factor Ets1 is widely expressed in developing organs and tissues, including the NC. In the chick, Ets1 is required for the expression of Sox10, a transcription factor critical for the development of various NC derivatives, including melanocytes. We show that Ets1 is required early for murine NC cell and melanocyte precursor survival in vivo. Given the importance of Ets1 for Sox10 expression in the chick, we investigated a potential genetic interaction between these genes by comparing the hypopigmentation phenotypes of single and double heterozygous mice. The incidence of hypopigmentation in double heterozygotes was significantly greater than in single heterozygotes. The area of hypopigmentation in double heterozygotes was significantly larger than would be expected from the addition of the areas of hypopigmentation of single heterozygotes, suggesting that Ets1 and Sox10 interact synergistically in melanocyte development. Since Sox10 is also essential for enteric ganglia development, we examined the distal colons of Ets1 null mutants and found a significant decrease in enteric innervation, which was exacerbated by Sox10 heterozygosity. At the molecular level, Ets1 was found to activate an enhancer critical for Sox10 expression in NC-derived structures. Furthermore, enhancer activation was significantly inhibited by the variable spotting mutation. Together, these results suggest that Ets1 and Sox10 interact to promote proper melanocyte and enteric ganglia development from the NC.

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Section: Discussionmentioning

confidence: 99%

The transcription factors Ets1 and Sox10 interact during murine melanocyte development

Saldana-Caboverde

Perera

Watkins‐Chow

et al. 2015

Developmental Biology

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“…Pax3 is able to inhibit the expression of trp2 , responsible for the conversion of L-dopachrome into 5,6-dihydroxyindole-2-carboxylate. This ensures high levels of mitf expression to induce melanocyte differentiation [29], [30] but at the same time prevents terminal differentiation. In the presence of β-catenin, the action of pax3 to block trp2 transcription is missing [31] and then trp2 contributes to melanocyte differentiation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…8). As occurs with mitf, pax3 also promotes and inhibits melanogenesis through transcriptional regulation of cKit [30]. CKit plays a critical role in melanocyte physiology by influencing melanogenesis, migration and survival of these cells [32] and it is primarily expressed in the melanized melanophores [13].…”

Section: Discussionmentioning

confidence: 99%

Morphological and Molecular Characterization of Dietary-Induced Pseudo-Albinism during Post-Embryonic Development of Solea senegalensis (Kaup, 1858)

et al. 2013

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The appearance of the pseudo-albino phenotype was investigated in developing Senegalese sole (Solea senegalensis, Kaup 1858) larvae at morphological and molecular levels. In order to induce the development of pseudo-albinos, Senegalese sole larvae were fed Artemia enriched with high levels of arachidonic acid (ARA). The development of their skin pigmentation was compared to that of a control group fed Artemia enriched with a reference commercial product. The relative amount of skin melanophores, xanthophores and iridophores revealed that larval pigmentation developed similarly in both groups. However, results from different relative proportions, allocation patterns, shapes and sizes of skin chromatophores revealed changes in the pigmentation pattern between ARA and control groups from 33 days post hatching onwards. The new populations of chromatophores that should appear at post-metamorphosis were not formed in the ARA group. Further, spatial patterns of distribution between the already present larval xanthophores and melanophores were suggestive of short-range interaction that seemed to be implicated in the degradation of these chromatophores, leading to the appearance of the pseudo-albino phenotype. The expression profile of several key pigmentation-related genes revealed that melanophore development was promoted in pseudo-albinos without a sufficient degree of terminal differentiation, thus preventing melanogenesis. Present results suggest the potential roles of asip1 and slc24a5 genes on the down-regulation of trp1 expression, leading to defects in melanin production. Moreover, gene expression data supports the involvement of pax3, mitf and asip1 genes in the developmental disruption of the new post-metamorphic populations of melanophores, xanthophores and iridophores.

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“…To determine the physiological role of Kit, we analysed the metabolic phenotypes of the Wps mouse strain, which carries a loss-of-function mutation in the Kit gene 25 . The Wps mutation does not affect the splicing of GNNK À versus GNNK þ Kit, but does significantly inhibit tyrosine kinase activity and downstream Akt and Erk signalling of Kit both in vitro and in vivo ( Supplementary Fig.…”

Section: Scf/kit Expression Is Altered In Obese Animals and Humansmentioning

confidence: 99%

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

Huang

Ruan

et al. 2014

Nat Commun

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Cell growth is tightly coupled with mitochondrial biogenesis in order to maintain energy and organelle homeostasis. Receptor tyrosine kinase Kit and its ligand, stem cell factor (SCF), play a critical role in the growth and survival of multiple cell lineages. Here we report that the expression of SCF and Kit in adipose tissues is responsive to food availability and environmental temperature, and is altered in obese mice and human patients. Mice carrying a lossof-function mutation in Kit develop obesity as a result of decreased energy expenditure. These phenotypes are associated with reduced PGC-1a expression and mitochondrial dysfunction in brown adipose tissue and skeletal muscle. We further demonstrate that SCF/Kit directly promotes Ppargc1a transcription and mitochondrial biogenesis. Blocking Kit signalling in mice decreases PGC-1a expression and thermogenesis, while overexpressing SCF systemically or specifically in brown adipose tissue increases thermogenesis and reduces weight gain. Collectively, these data provide mechanistic insight into the regulation of mitochondrial function by SCF/Kit signalling and lay a foundation for exploring SCF/Kit signalling as a therapeutic target for metabolic diseases.

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Identification of a novel nonsense mutation on the Pax3 gene in ENU-derived white belly spotting mice and its genetic interaction with c-Kit

Cited by 14 publications

References 53 publications

The transcription factors Ets1 and Sox10 interact during murine melanocyte development

The transcription factors Ets1 and Sox10 interact during murine melanocyte development

Morphological and Molecular Characterization of Dietary-Induced Pseudo-Albinism during Post-Embryonic Development of Solea senegalensis (Kaup, 1858)

The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure

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