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Pdgfra) Is Deleted in the Mouse Patch (Ph) Mutation (Development/Dominant Spotting/Linkage Analysis/Human Homolog) DENNIS A

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Pdgfra) Is Deleted in the Mouse Patch (Ph) Mutation (Development/Dominant Spotting/Linkage Analysis/Human Homolog) DENNIS A Proc. Nati. Acad. Sci. USA Vol. 88, pp. 6-10, January 1991 Genetics Platelet-derived growth factor receptor a-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation (development/dominant spotting/linkage analysis/human homolog) DENNIS A. STEPHENSON*, MARK MERCOLAt, ELIZABETH ANDERSON*, CHIAYENG WANGt, CHARLES D. STILESt, DANIEL F. BOWEN-POPEt, AND VERNE M. CHAPMAN*§ *Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; tDivision of Cellular and Molecular Biology, Dana-Farber Cancer Institute, and Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115; and :Department of Pathology, University of Washington, Seattle, WA 98195 Communicated by M. F. Lyon, October 1, 1990 (receivedfor review July 30, 1990) ABSTRACT Platelet-derived growth factor receptors are Presumptive homozygotes, produced in crosses between composed of two subunits (a and (3) that associate with one heterozygotes, display gross anatomical abnormalities and another to form three functionally active dimeric receptor die midway through gestation (7). The Ph locus was shown to species. The two subunits are encoded by separate loci in be distinct from the W locus by both complementation and humans and other species. In this study, we used conventional recombinational linkage analysis (7). When Ph heterozygotes interspecific backcross mapping and an analysis ofa deletional were crossed to viable dominant spotting (W") heterozy- mutation to establish close linkage between the a-subunit gene gotes, no offspring with the characteristic black-eyed phe- (Pdgfra) and the dominant spotting (W) locus on mouse chro- notype were observed that might have suggested allelism. mosome 5. Further, by analyzing the restriction fragment However, approximately one-fourth of the offspring had a length polymorphisms in interspecific F1 hybrids, we were able more extensive spotting phenotype than either Ph or W" to demonstrate that the closely associated patch (Ph) locus alone, suggesting that they were probably the double het- carries a deletion in Pdgfra. This observation was confirmed by erozygotes (i.e., Ph +/+ W"). Hematological analysis of the both DNA and RNA analysis of 10.5-day fetuses produced from double heterozygotes showed no enhancement ofthe anemia crosses between Ph heterozygotes. Out of 16 fetuses analyzed, associated with the W" mutation alone. Although the Ph Pdgfra genomic sequences were absent and no mRNA for the locus is distinct from the W locus, it does fall within the receptor was detected in 6 fetuses that were developmentally deletion defined by the W19H mutant allele, unlike the closely abnormal (the presumptive Ph homozygotes). We also deter- associated Rw locus (8). mined that the deletion associated with the Ph mutation does The platelet-derived growth factor receptor (PDGFR) is not extend into the coding sequences of the adjacent Kit gene, functionally active as a homodimer or heterodimer of two by analysis of the genomic DNA from both the interspecific F1 different protein subunits identified as a and p. The genes hybrids and the presumptive Ph homozygotes. The absence of (PDGFRA and PDGFRB) encoding these subunits map to Pdgfra genomic sequences and the lack of detectable message human chromosomes 4 and 5, respectively (9-11). In situ associated with the Ph mutation should make this mutant a hybridization analysis localized PDGFRA to the same region valuable asset for understanding the role of the receptor a of human chromosome 4 as the c-kit protooncogene. Since subunit during mammalian development. this region of human chromosome 4 is homologous with mouse chromosome 5, it was probable that the mouse Pdgfra A series of semidominant mutations that cause white spotting gene would also map to the same region as the KitiW locus. in the mouse are closely linked to one another on chromo- We reasoned that ifPdgfra did map to this region, it might be some 5. Included in this cluster are the loci for dominant related to other mutant loci in the region that affect mam- spotting (W), patch (Ph), and rump-white (Rw). Close genetic malian development. linkage between the W locus and the c-kit protooncogene Here we show that Pdgfra is closely linked to WiKit on (Kit), which encodes a transmembrane tyrosine kinase, was mouse chromosome 5. We also provide evidence from South- demonstrated by Chabot et al. (1). Geissler et al. (2) con- ern analysis of interspecific F1 hybrids that the Ph mutation firmed this association by demonstrating that Kit genomic carries a deletion in the genomic sequences associated with sequences were altered in two W mutants (W44J and WX) and Pdgfra. This observation is supported by DNA and RNA that the mRNA level was reduced in one of them (W44I). analysis of 10.5-day fetuses obtained from intercrossing Ph Subsequent analysis of various W mutant alleles showed that heterozygotes. Presumptive Ph homozygotes were shown to the W locus encodes the Kit gene product (3-6). Further- lack the Pdgfra genomic sequences. Furthermore, no Pdgfra more, the severity of the phenotypic defects associated with mRNA expression was detected in these abnormal fetuses. the various mutant alleles could be correlated with the nature Kit gene analysis of both the interspecific F1 hybrids and the of the mutational event by assuming that Kit encodes a Ph homozygotes indicates that the deletion does not extend receptor that is functionally active as a dimeric molecule. into these coding sequences. Specifically, mutations that abolish tyrosine kinase activity (W37J, Wv/W55J, W41J, and W42") have a more severe het- erozygous phenotype than those mutants (W and WI9H) that METHODS result in loss of the receptor. Mice. Laboratory stocks carrying either the sash (Wsh) Patch heterozygotes (Ph/+) have a spotting phenotype allele at the dominant spotting locus (12), the W19H deletional that is similar to those of some of the W mutant alleles, mutation (8), or the patch (Ph) mutant allele (7) were obtained although there is no evidence of a hematological defect (7). from the Medical Research Council Radiobiology Unit (Chil- The publication costs of this article were defrayed in part by page charge Abbreviations: PDGF, platelet-derived growth factor; PDGFR, payment. This article must therefore be hereby marked "advertisement" PDGF receptor. in accordance with 18 U.S.C. §1734 solely to indicate this fact. §To whom reprint requests should be addressed. 6 Downloaded by guest on September 28, 2021 Genetics: Stephenson et al. Proc. Natl. Acad. Sci. USA 88 (1991) 7 ton, U.K.). Both the WAh and W19H mutations occurred on a Preliminary characterization of the clone indicates that it C3H x 101 F1 hybrid background; however, during the lacks -0.8 kb from the start of the open reading frame maintenance of the Wsh mutation it was transferred onto a (unpublished data). The Pdgfra gene was identified with C57BL/6J.bg congenic background. The Ph mutation oc- either a 1.5-kb cDNA encoding the second tyrosine kinase curred on a C57BL background and was transferred onto a domain and =1.0 kb of untranslated message (the 3' cDNA) CBA strain background but is now maintained on a C3H x or a 6.4-kb full-length cDNA (17). 101 F1 hybrid background. Wild-derived Mus musculus RNA Analysis. RNA was assayed for specific gene expres- (PWK stock) and Mus spretus used to produce interspecific sion by RNase protection assay using antisense transcripts F1 hybrids were originally obtained from trappings in Czech- synthesized in vitro in the presence of [a-32P]CTP (18). oslovakia and Spain, respectively. PWK is a partially inbred Transcript templates for mouse PDGF a ligand (PDGF A stock whereas the M. spretus stock is maintained as an chain) and PDGFR a chain were as described (17). Probe outbred colony. transcripts (106 cpm) were hybridized to each RNA sample Mouse Crosses and Backcrosses. The interspecific back- for 16 hr and then digested with RNases A and T1 (Pharmacia cross offspring used in the linkage analysis were as described or Boehringer Mannheim). Protected fragments were ana- by Chabot et al. (1). A laboratory stock homozygous for the lyzed in a 6% polyacrylamide/8 M urea gel. The radioactivity sash and beige coat pigment mutations (Wsh/Wsh bg/bg) was in the protected bands was quantitated by exposing the dried crossed to the wild-derived PWK stock and the F1 hybrids gel to a PhosphorImager (Molecular Dynamics, Sunnyvale, were backcrossed to the C57BL/6J.bg congenic strain. In- CA). terspecific F1 hybrids were produced between (i) the W19H mutant stock and M. spretus and (ii) Ph mutant heterozy- gotes and the wild-derived PWK stock. Patch heterozygotes RESULTS were intercrossed (Ph/+ x Ph/+) to produce Ph homozy- Pdgfra Is Closely Linked to W. Genomic DNA from the gotes. Since the homozygotes die midway through gestation parental mouse stocks (C57BL, C3H, CBA, 101, and PWK) (7), the pregnant females were sacrificed 10 days after the was analyzed for restriction fragment length polymorphism observation of a vaginal plug (day 0.5 of gestation). with the 3' cDNA probe to the mouse Pdgfra gene. No All live offspring were classified for their pigment gene variation was observed between the laboratory strains and phenotypes prior to dissection. Sash heterozygotes (Wsh/+) the wild-derived PWK stock with the restriction endonu- had a broad white band across the loins in the interspecific cleases BamHI, Bgl II, EcoRI, HindIII, and Pvu II. How- backcross offspring, characteristic of the phenotype de- ever, variation was observed with the restriction endonu- scribed by Lyon and Glenister (12). Similarly, the spotted cleases EcoRV and Pst I. An EcoRV fragment of 23 kb phenotype associated with the Ph heterozygotes (7) was identified the C57BL allele (and other laboratory strains unequivocal in the interspecific F1 hybrids. However, the tested), whereas a 20-kb fragment defined the PWK allele.
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