Development 115, 289-303 (1992) Printed in Great Britain © The Company of Biologists Limited 1992 289 Developmental expression of the a receptor for platelet-derived growth factor, which is deleted in the embryonic lethal Patch mutation AVI ORR-URTREGER 1 , MARK T. BEDFORD 1 , MYOUNG-SOOL DO 2 , LEA EISENBACH 2 and PETER LONAI 1 * Departments of ' Chemical Immunology and 2 Cell Biology, The Weumann Institute of Science, Rehovot 76100, Israel •Author for correspondence Summary The a receptor of PDGF (Pdgfra) is expressed in primitive endoderm and mesoderm derivatives through- out embryogenesis. In the early primitive streak stage the gene is transcribed in the visceral and parietal endoderm. Later it is expressed in the presomitic mesoderm, yolk sac and amnion. During somitogenesis its transcription localizes to the heart and the somites. Subsequently, it is transcribed in the dermatome, the sclerotome, the developing limb and in various mes- enchymal tissues of visceral organs. Its wild-type expression pattern correlates well with the phenotype of homozygous mutant Patch (Ph) embryos, where the Pdgfra gene is deleted. 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. Most Ph/Ph embryos die before the 11 day of gestation. Those that survive till early organogenesis are very small, have hypertrophic yolk sacs, small and undiffer- entiated somites, convoluted neural tubes, large heart and pericardium, rudimentary limb buds and branchial arches. Our observations together suggest that the a PDGF receptor may be required for the normal development of visceral endoderm and mesoderm derivatives. Key words: PDGF receptor, embryogenesis, in situ hybridization, Ph mutation, embryonic lethality Introduction PDGF (platelet-derived growth factor) is a major mitogen for connective tissue and glial cells in vitro (reviewed by Ross et al., 1986 and by Heldin and Westermark, 1989). It stimulates chemotaxis, it is possibly active in wound healing and it is thought to be involved in the development of atherosclerotic plaques (Rubin et al., 1988; Ferns et al., 1991). Abnormal regulation of PDGF, due to mutation or overexpres- sion, can contribute to malignant growth and both the B and A chains of PDGF can cause malignant transform- ation (Beckmann et al., 1988). A derivative of PDGF- B, the \-sis oncogene, transforms cells that express the PDGF receptor (Downward et al., 1984; Heldin and Westermark, 1989). The role of PDGF in cell differen- tiation was demonstrated in the glial cells of the optic nerve, where PDGF is produced by type 1 astrocytes, acts on bipotential glial progenitor cells, and is required for the timing of their differentiation into oligodendro- cytes (Noble et al., 1988; Raff et al., 1988). PDGF is also expressed in embryonic carcinoma cells (Gudas et al., 1983), m the extraembryonic membranes and in the placenta (Goustin et al., 1985), suggesting that it may have a role in embryogenesis. Numerous other polypeptide growth factors, such as those belong- ing to the FGF and the TGF/3 gene family, are active in mesoderm induction, as detected by the Xenopus animal cap model. PDGF however has no detectable effect in this system (Smith, 1989; Whitman and Melton, 1989), which may be one reason why we know comparatively little about its role in early development. Biochemical analysis revealed that PDGF and its receptor (PDGF-R) each have two isoforms, desig- nated A and B for the growth factor, a and /S for the receptor. PDGF and PDGF-R isoforms function as dimers, and both homo- and heterodimers are formed. The a-receptor (Pdgfra) recognizes the A and B chains, whereas the /S receptor (Pdgfrb) is specific for PDGF-B. The PDGF AA homodimer is recognized exclusively by the era-receptor homodimer (Seifert et al., 1989; Heldin et al., 1988). Recent evidence drew attention to the involvement of Pdgfra in early development. Mercola et al. (1989) showed that Pdgfra and PDGF-A are expressed prior to Pdgfrb and PDGF-B in the 7.5- to 8.5-day-old mouse embryo, suggesting that Pdgfra and PDGF-A may have special roles at the primitive streak stage. RFLP