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Gene Review

Ph  -  patch deletion region

Mus musculus

 
 
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Disease relevance of Ph

 

High impact information on Ph

  • The receptor tyrosine kinases (RTKs) c-kit and platelet-derived growth factor receptor alpha chain (PDG-FRa) are encoded at the white spotting (W) and patch (Ph) loci on mouse chromosome 5 [3].
  • While W mutations affect melanogenesis, gametogenesis, and hematopoiesis, the Ph mutation affects melanogenesis and causes early lethality in homozygotes [3].
  • Moreover, we have defined the organization of the RTKs in the W/Ph region on chromosome 5 and characterized the Wsh mutation by using pulsed-field gel electrophoresis [3].
  • Therefore, positive 5' upstream elements controlling c-kit expression in mast cells and some other cell types are affected by the Wsh mutation and negative elements are affected by both the Wsh and the Ph mutation [3].
  • The map indicates the position of the Ph deletion, which encompasses not more than 400 kb around and including the Pdgfra gene [4].
 

Biological context of Ph

  • Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5 [4].
  • The structural analysis of chromosomal rearrangements associated with W19H, Ph, and Rw combined with the high-resolution physical mapping points the way toward the definition of these mutations in molecular terms and isolation of homologous genes on human chromosome 4 [4].
  • Although dermal mesenchyme is adversely affected in Ph homozygotes, SlF mRNA expression by the cells of the dermatome is normal in Ph embryos when neural crest-derived MPs start to migrate on the lateral pathway [5].
  • The Patch (Ph) mutation in the mouse, a deletion that includes the gene for PDGFR alpha, is a recessive lethal that exhibits a dominant pigment phenotype in heterozygotes [5].
  • In order to assess whether this decrease affects the motile activity of mesenchymal cells, cell migration from Ph/Ph branchial arch explants was compared to migration from normal arch tissue and found to be significantly less [6].
 

Anatomical context of Ph

  • To assess whether the Ph mutation acts cell-autonomously or non-autonomously on melanocyte development, we have examined the melanogenic potential of neural crest populations from normal and mutant crest cells in vitro and the pattern of dispersal and survival of melanocyte precursors (MPs) in vivo [5].
  • In contrast, mRNA for the SlF receptor, c-kit, was observed to be ectopically expressed in somites and lateral mesenchyme in embryos carrying the Ph mutation [5].
  • This observation was confirmed by both DNA and RNA analysis of 10.5-day fetuses produced from crosses between Ph heterozygotes [7].
  • The results show a 65-70% decrease in motor and sensory neuron numbers in Ph/Ph mice, compared to controls, at all stages examined [2].
  • Ph/Ph vessels appear to be lined with a normal endothelium, but contain a reduced number of smooth muscle cells and are fragile during processing for histology [8].
 

Associations of Ph with chemical compounds

  • Thus the W19H deletion removes at least two receptor tyrosine kinases and the results suggest Pdgfra as a candidate for the Ph locus [9].
 

Enzymatic interactions of Ph

  • Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation [7].
 

Regulatory relationships of Ph

  • In vivo, homozygous Ph embryos contain a subpopulation of crest-derived cells that express c-kit and tyrosinase-related protein-2 characteristic of MPs [5].
  • Both mesodermally derived and neural crest-derived components of the cardiovascular system are severely dysmorphic in Ph/Ph embryos and those structures most severely affected are those that normally express alpha PDGFR mRNA at the highest levels and for the longest duration [8].
 

Other interactions of Ph

  • The mouse W19H mutation is an x-ray-induced deletion of more than 2 centimorgans on chromosome 5 encompassing the white spotting mutation W (encoded by the Kit protooncogene), patch (Ph), and recessive lethal (l) loci [9].
  • Together, these results suggest that PDGF-A regulates MMP-2 expression and activation during normal development and that faulty proteinase expression may be at least partially responsible for the developmental defects exhibited by Ph/Ph embryos [6].
  • We report that trunk neural crest cells from homozygous Ph embryos give rise to pigmented melanocytes in vitro in response to Steel factor (SlF) [5].
  • However, it is not clear whether there are differences in expression of PDGF receptor alpha-subunit (PDGFR-alpha) in brain tissue of the Patch heterozygous (Ph/+) mutants compared to wild-type C57Bl (+/+) mice [10].
  • The Ph phenotype is first detectable at the primitive streak stage with convoluted and hypertrophic visceral yolk sac, deformed neural plate and disorganized or missing mesoderm [11].
 

Analytical, diagnostic and therapeutic context of Ph

  • In this report we evaluate the role of alpha PDGFR in cardiovascular development by using in situ hybridization to follow the changing pattern of alpha PDGFR expression in cardiovascular tissues after embryonic day 13, and comparing this pattern with the pattern of cardiovascular defects observed in homozygous Ph mutants [8].

References

  1. Spina bifida occulta in homozygous Patch mouse embryos. Payne, J., Shibasaki, F., Mercola, M. Dev. Dyn. (1997) [Pubmed]
  2. Altered development of spinal cord in the mouse mutant (Patch) lacking the PDGF receptor alpha-subunit gene. Li, L., Schatteman, G.C., Oppenheim, R.W., Lei, M., Bowen-Pope, D.F., Houenou, L.J. Brain Res. Dev. Brain Res. (1996) [Pubmed]
  3. The Wsh and Ph mutations affect the c-kit expression profile: c-kit misexpression in embryogenesis impairs melanogenesis in Wsh and Ph mutant mice. Duttlinger, R., Manova, K., Berrozpe, G., Chu, T.Y., DeLeon, V., Timokhina, I., Chaganti, R.S., Zelenetz, A.D., Bachvarova, R.F., Besmer, P. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. Structural analysis of chromosomal rearrangements associated with the developmental mutations Ph, W19H, and Rw on mouse chromosome 5. Nagle, D.L., Martin-DeLeon, P., Hough, R.B., Bućan, M. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  5. Ectopic c-kit expression affects the fate of melanocyte precursors in Patch mutant embryos. Wehrle-Haller, B., Morrison-Graham, K., Weston, J.A. Dev. Biol. (1996) [Pubmed]
  6. Diminished matrix metalloproteinase 2 (MMP-2) in ectomesenchyme-derived tissues of the Patch mutant mouse: regulation of MMP-2 by PDGF and effects on mesenchymal cell migration. Robbins, J.R., McGuire, P.G., Wehrle-Haller, B., Rogers, S.L. Dev. Biol. (1999) [Pubmed]
  7. Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation. Stephenson, D.A., Mercola, M., Anderson, E., Wang, C.Y., Stiles, C.D., Bowen-Pope, D.F., Chapman, V.M. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Platelet-derived growth factor receptor alpha subunit deleted Patch mouse exhibits severe cardiovascular dysmorphogenesis. Schatteman, G.C., Motley, S.T., Effmann, E.L., Bowen-Pope, D.F. Teratology (1995) [Pubmed]
  9. Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5. Smith, E.A., Seldin, M.F., Martinez, L., Watson, M.L., Choudhury, G.G., Lalley, P.A., Pierce, J., Aaronson, S., Barker, J., Naylor, S.L. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  10. Expression of platelet-derived growth factor (PDGF) receptor alpha-subunit in mouse brain: comparison of Patch mutants and normal littermates. Zhang, F.X., Hutchins, J.B. Cell. Mol. Neurobiol. (1996) [Pubmed]
  11. Developmental expression of the alpha receptor for platelet-derived growth factor, which is deleted in the embryonic lethal Patch mutation. Orr-Urtreger, A., Bedford, M.T., Do, M.S., Eisenbach, L., Lonai, P. Development (1992) [Pubmed]
 
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