International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 17 - ESSENTIAL FUNCTIONS OF THE PHOSPHATIDYLSERINE RECEPTOR (PTDSR) DURING EMBRYOGENESIS, DISTINCT FROM APOPTOTIC CELL REMOVAL

Böse J 1, Gruber AD 2, Helming L. 1, Schiebe S 1, Wegener I 1, Hafner M 3, Horsch M 4, Clarke K 5, Neubauer S 5, Schneider JE 5, Beckers J 4, Bhattacharya S 5, Lengeling A 1

1 Junior Research Group Infection Genetics,  German Research Centre for Biotechnology (GBF), Braunschweig, Germany, 2 Department of Pathology, School of Veterinary Medicine Hannover, Hannover, Germany, 3 Department of Experimental Immunology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany, 4 Institute of Experimental Genetics, GSF - National Research Centre for Environment and Health, Neuherberg, Germany, 5 Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom

Apoptosis and phagocytosis of apoptotic cells are fundamental processes for normal animal development, homeostasis and immune function. Among the described receptors on phagocytes for the efficient recognition and engulfment of apoptotic cells, the phosphatidylserine receptor (Ptdsr) has been particularly implicated in apoptotic cell removal. To determine the function of Ptdsr in vivo, we generated a null allele in the mouse and established a Ptdsr-b-geo gene-trap line. Targeted inactivation of Ptdsr causes perinatal lethality that is associated with growth retardation and a delay in the terminal differentiation of kidney, intestine, liver and lung. Interestingly, about 14 % of Ptdsr -/- mice are anophthalmic and display fundamentally novel lesions, with induction of ectopic retinal pigmented epithelium in paranasal sinuses. By using the gene-trap mouse line we found that Ptdsr has specific and prominent expression patterns in organs that are affected by Ptdsr-deficiency. Moreover, by using high-resolution magnetic resonance imaging (MRI) we identified ventricular septal defects, double-outlet right ventricle and hypoplasia of the pulmonary artery in mutant embryos, suggesting that Ptdsr -/- mice die due to heart malformations. These results indicate that Ptdsr plays a hitherto unexpected role in cellular differentiation during organ morphogenesis and especially in cardiovascular development. To our surprise we found normal engulfment of apoptotic cells in Ptdsr knockout mice, demonstrating that Ptdsr has essential, novel functions during embryogenesis, distinct from apoptotic cell removal. Recent molecular analysis and expression profiling studies are supporting the function of Ptdsr as a key factor for the control of multiple molecular pathways required for organogenesis.

This work is supported by the EU project EUMORPHIA (QLG2-CT-2002-00930, grant to A.L.) and by the German National Genome Research Network (NGFN-Xpress, grant to J.B.)

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