A PDGF receptor mutation in the mouse (Patch) perturbs the development of a non-neuronal subset of neural crest-derived cells.

The Patch (Ph) mutation in mice is a deletion of the gene encoding the platelet-derived growth factor receptor alpha subunit (PDGFR alpha). Patch is a recessive lethal recognized in heterozygotes by its effect on the pattern of neural crest-derived pigment cells, and in homozygous mutant embryos by visible defects in craniofacial structures. Since both pigment cells and craniofacial structures are derived from the neural crest, we have examined the differentiation of other crest cell-derived structures in Ph/Ph mutants to assess which crest cell populations are adversely affected by this mutation. Defects were found in many structures populated by non-neuronal derivatives of cranial crest cells including the thymus, the outflow tract of the heart, cornea, and teeth. In contrast, crest-derived neurons in both the head and trunk appeared normal. The expression pattern of PDGFR alpha mRNA was determined in normal embryos and was compared with the defects present in Ph/Ph embryos. PDGFR alpha mRNA was expressed at high levels in the non-neuronal derivatives of the cranial neural crest but was not detected in the crest cell neuronal derivatives. These results suggest that functional PDGF alpha is required for the normal development of many non-neuronal crest-derived structures but not for the development of crest-derived neuronal structures. Abnormal development of the non-neuronal crest cells in Ph/Ph embryos was also correlated with an increase in the diameter of the proteoglycan-containing granules within the crest cell migratory spaces. This change in matrix structure was observed both before and after crest cells had entered these spaces. Taken together, these observations suggest that functional PDGFR alpha can affect crest development both directly, by acting as a cell growth and/or survival stimulus for populations of non-neurogenic crest cells, and indirectly, by affecting the structure of the matrix environment through which such cells move.

[1]  C. Steele,et al.  Serum variants causing the formation of double hearts and other abnormalities in explanted rat embryos. , 1974, Journal of embryology and experimental morphology.

[2]  D. Newgreen,et al.  The migration of neural crest cells. , 1986, International review of cytology.

[3]  O. Witte.  Steel locus defines new multipotent growth factor , 1990, Cell.

[4]  D. Cockroft,et al.  Comparison of growth in vitro and in vivo of post-implantation rat embryos. , 1976, Journal of embryology and experimental morphology.

[5]  C. Cordon-Cardo,et al.  Sensory neuronopathy and small cell lung cancer. Antineuronal antibody that also reacts with the tumor. , 1986, The American journal of medicine.

[6]  D A Stephenson,et al.  Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[7]  C. Humphrey,et al.  A simple methylene blue-azure II-basic fuchsin stain for epoxy-embedded tissue sections. , 1974, Stain technology.

[8]  J. A. Weston,et al.  Association between collagen and glycosaminoglycans is altered in dermal extracellular matrix of fetal Steel (Sld/Sld) mice. , 1990, Developmental biology.

[9]  P. Leder,et al.  Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the SId mutant , 1991, Cell.

[10]  J. A. Weston,et al.  Substratum effects on cell dispersal, morphology, and differentiation in cultures of avian neural crest cells. , 1990, Developmental biology.

[11]  D. Noden.  Patterns and organization of craniofacial skeletogenic and myogenic mesenchyme: a perspective. , 1982, Progress in clinical and biological research.

[12]  J. A. Weston,et al.  Extracellular matrix from normal but not Steel mutant mice enhances melanogenesis in cultured mouse neural crest cells. , 1990, Developmental biology.

[13]  D. Noden.  Interactions and fates of avian craniofacial mesenchyme. , 1988, Development.

[14]  G. Hascall,et al.  Cartilage proteoglycans: comparison of sectioned and spread whole molecules. , 1980, Journal of ultrastructure research.

[15]  J. Pintar.  Distribution and synthesis of glycosaminoglycans during quail neural crest morphogenesis. , 1978, Developmental biology.

[16]  M. Forbes,et al.  Exogenous basement-membrane-like matrix stimulates adrenergic development in avian neural crest cultures. , 1987, Development.

[17]  E. Kollar,et al.  Tissue interactions in embryonic mouse tooth germs. II. The inductive role of the dental papilla. , 1970, Journal of embryology and experimental morphology.

[18]  R. Markwald,et al.  Myocardial specificity for initiating endothelial-mesenchymal cell transition in embryonic chick heart correlates with a particulate distribution of fibronectin. , 1987, Developmental biology.

[19]  M. A. Hayat,et al.  Fixation for Electron Microscopy , 1982 .

[20]  H. Grüneberg,et al.  Two closely linked genes in the mouse. , 1960 .

[21]  M. Marusich,et al.  Identification of early neurogenic cells in the neural crest lineage. , 1992, Developmental biology.

[22]  W. Snider,et al.  PDGF A-chain gene is expressed by mammalian neurons during development and in maturity , 1991, Cell.

[23]  R. Perris,et al.  Local embryonic matrices determine region-specific phenotypes in neural crest cells. , 1988, Science.

[24]  R. Perris,et al.  Promotion of chromatophore differentiation in isolated premigratory neural crest cells by extracellular matrix material explanted on microcarriers. , 1986, Developmental biology.

[25]  R. Tucker,et al.  Pigment cell pattern formation in Taricha torosa: the role of the extracellular matrix in controlling pigment cell migration and differentiation. , 1986, Developmental biology.

[26]  M. Kirby,et al.  Dependence of thymus development on derivatives of the neural crest. , 1984, Science.

[27]  T. Parkening,et al.  A METHOD FOR SEQUENTIAL HIGH RESOLUTION LIGHT AND ELECTRON MICROSCOPY OF SELECTED AREAS OF THE SAME MATERIAL , 1974, The Journal of cell biology.

[28]  B. K. Hartman,et al.  Importance of fixation in immunohistochemistry: use of formaldehyde solutions at variable pH for the localization of tyrosine hydroxylase. , 1981, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[29]  J. A. Weston,et al.  Mouse mutants provide new insights into the role of extracellular matrix in cell migration and differentiation. , 1989, Trends in genetics : TIG.

[30]  M. Kirby,et al.  Neural crest cells contribute to normal aorticopulmonary septation. , 1983, Science.

[31]  M. Rosenblum,et al.  Expression of an antigen in small cell lung carcinoma lines detected by antibodies from patients with paraneoplastic dorsal root ganglionpathy. , 1988, Cancer research.

[32]  E. Hay.  Development of the vertebrate cornea. , 1980, International review of cytology.

[33]  M. Waterfield,et al.  Platelet-derived growth factor promotes division and motility and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell. , 1988, Nature.

[34]  C. Erickson,et al.  An SEM analysis of neural crest migration in the mouse. , 1983, Journal of embryology and experimental morphology.

[35]  T. Sadler,et al.  Culture of early somite mouse embryos during organogenesis. , 1979, Journal of embryology and experimental morphology.

[36]  J. Loring,et al.  Extracellular matrix materials influence quail neural crest cell differentiation in vitro. , 1982, Developmental biology.

[37]  D. Noden,et al.  Contributions of placodal and neural crest cells to avian cranial peripheral ganglia. , 1983, The American journal of anatomy.

[38]  A. Miles.  Embryonic tooth formation; a tool for developmental biology , 1974 .