Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5.

Nagle, Deborah L.; Martin‐DeLeon, Patricia A.; Hough, Richard B.; Bućan, Maja

doi:10.1073/pnas.91.15.7237

Cited by 39 publications

(26 citation statements)

References 33 publications

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“…In summary, Kit expression is restricted to distinct cell types in which the Kit receptor functions. Studies of the mechanisms that control cell typespecific Kit expression are therefore of great significance.The Kit RTK is encoded at the white spotting (W) locus on mouse chromosome 5 in the vicinity of the RTKs PDGFR␣ and flk1 and comprises 21 exons contained in 70 kb (13,19,20,39,40). Many W mutations affecting Kit structure and function have been identified and characterized; the analysis of expression mutations has provided some insight into the mechanism of tissue-specific Kit expression.…”

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confidence: 99%

A Distant Upstream Locus Control Region Is Critical for Expression of the Kit Receptor Gene in Mast Cells

Berrozpe¹,

Agosti²,

Tucker³

et al. 2006

Molecular and Cellular Biology

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The Kit receptor tyrosine kinase functions in hematopoiesis, melanogenesis, and gametogenesis and in interstitial cells of Cajal. We previously identified two upstream hypersensitive site (HS) clusters in mast cells and melanocytes. Here we investigated the roles of these 5 HS sequences in Kit expression using transgenic mice carrying Kit-GFP reporter constructs. In these mice there is close correspondence between Kit-GFP reporter and endogenous Kit gene expression in most tissues analyzed. Deletion analysis defined the 5 upstream HS cluster region as critical for Kit expression in mast cells. Furthermore, chromatin immunoprecipitation analysis in mast cells showed that H3 and H4 histone hyperacetylation and RNA polymerase II recruitment within the Kit promoter and in the 5 HS region were associated with Kit expression. Therefore, the 5 upstream hypersensitivity sites appear to be critical components of locus control region-mediated Kit gene activation in mast cells.Differential control of gene expression during embryonic development and in the adult organism is mediated by the interaction of the transcription machinery with cis regulatory elements located at the promoter, upstream, or in intronic sequences of a gene. The mechanism by which tissue-specific gene expression is achieved involves the action of transcription factors together with changes in chromatin structure. Chromatin structure is a major determinant of gene expression, and mechanisms of chromatin remodeling are critical components of its regulation. Whereas SWI/SNF-like chromatin-remodeling ATPases disrupt histone-DNA interactions, covalent Nterminal histone modifications, including acetylation, methylation, and phosphorylation, also have important roles in the remodeling of chromatin structure and the regulation of transcription (36). In this way histone modification patterns have been proposed to constitute a histone "code" which specifies downstream functions (45). Hyperacetylation and hypoacetylation of histones H3 and H4 correlate with open/accessible or closed/inaccessible chromatin structures, respectively, and transcriptional activation or repression (22, 31). Thus, the characterization of histone modification patterns has become an important tool in studies of gene expression.The Kit receptor tyrosine kinase (RTK) functions in distinct cell populations during embryonic development and in the postnatal animal (5, 6). During gametogenesis, Kit is expressed in primordial germ cells as they migrate from the allantois to the genital ridge (10, 35). Subsequently, during postnatal gametogenesis, Kit is expressed in spermatogonia and oocytes and in endocrine Leydig and thecal cells (2). In hematopoiesis during embryogenesis and in postnatal animals, Kit is expressed in hematopoietic stem cells and lineage progenitors, as well as in mast cells and eosinophils (5, 18, 48). In melanogenesis, Kit is expressed in migrating melanoblasts during embryonic development, in differentiated melanocytes in hair follicles, and in the gastrointestinal tract in ...

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confidence: 99%

A Distant Upstream Locus Control Region Is Critical for Expression of the Kit Receptor Gene in Mast Cells

Berrozpe¹,

Agosti²,

Tucker³

et al. 2006

Molecular and Cellular Biology

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“…22 and this publication). The proximal breakpoint of the Rw inversion lies centromeric to the En2 locus, whereas the distal breakpoint maps to the region between the Kit and Pdgfra genes in the central portion of the chromosome (14,22). These studies suggested that the dominant pigmentation defect in Rw also could be attributed to the long range effect on Kit expression in melanocyte precursors (14,19).…”

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“…The role of Kit in the intracellular signal transduction pathways in many distinct cell types is reflected by the pleiotropic affect of W on primordial germ cells, hematopoietic cells, melanocytes, and interstitial cells of Cajal in the small intestine, (9,10). The Ph mutation is associated with a deletion encompassing another receptor tyrosine kinase gene, Pdgfra (11)(12)(13)(14). Homozygous Ph͞Ph mice die between embryonic day (E) 9 and E 16 and show severe morphological anomalies (11,15), with some but not all anomalies observed in embryos with the targeted null-mutation for PDGF␣R (16).…”

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Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression

Hough

Lengeling

Bedian

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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The mouse rump white (Rw) mutation causes a pigmentation defect in heterozygotes and embryonic lethality in homozygotes. At embryonic day (E) 7.5, Rw͞Rw embryos are retarded in growth, fail to complete neurulation and die around E 9.5. The Rw mutation is associated with a chromosomal inversion spanning 30 cM of the proximal portion of mouse chromosome 5. The Rw embryonic lethality is complemented by the W 19H deletion, which spans the distal boundary of the Rw inversion, suggesting that the Rw lethality is not caused by the disruption of a gene at the distal end of the inversion. Here, we report the molecular characterization of sequences disrupted by both inversion breakpoints. These studies indicate that the distal breakpoint of the inversion is associated with ectopic Kit expression and therefore may be responsible for the dominant pigmentation defect in Rw͞؉ mice; whereas the recessive lethality of Rw is probably due to the disruption of the gene encoding dipeptidyl aminopeptidase-like protein 6,

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“…Rw is a large inversion terminating just upstream of Kit, and so may affect Kit expression (Nagle et al 1994), although expression is not lost . However, there is still no molecular information on rs.…”

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confidence: 99%

recessive spotting: a linked locus that interacts with W/Kit but is not allelic

et al. 1998

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Background: The murine coat-colour mutation recessive spotting (rs) maps very closely to the W/Kit locus, encoding the proto-oncoprotein Kit, the protein tyrosine kinase receptor for stem cell factor. Kit is important in the development of melanocytes, germ cells, interstitial cells of Cajal (ICC) and haemopoietic lineages, including mast cells. rs has never been genetically separated from Kit, and interacts with Kit mutations, suggesting that it is a recessive allele of Kit. Here we have tested this possibility. We have shown previously that diploid rs/rs melanocytes proliferated more slowly than did þ/þ melanocytes, as did an immortal line of rs/rs melanocytes, melan-rs.

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Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5.

Cited by 39 publications

References 33 publications

A Distant Upstream Locus Control Region Is Critical for Expression of the Kit Receptor Gene in Mast Cells

A Distant Upstream Locus Control Region Is Critical for Expression of the Kit Receptor Gene in Mast Cells

Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression

recessive spotting: a linked locus that interacts with W/Kit but is not allelic

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