Erythropoietin is an essential growth factor that promotes survival, proliferation, and differentiation of mammalian erythroid progenitor cells. Erythropoietin−/− and erythropoietin receptor−/− mouse embryos

Erythropoietin (EPO) is best known as an essential growth factor that regulates erythrocyte production in mammals (Krantz, 1991). Through specific binding to its cognate receptor, EPOR (D’Andrea et al., 1989), EPO triggers a chain of intracellular signaling events which depend on activation of Jak2 tyrosine kinase (Witthuhn et al., 1993). In addition to erythropoiesis, EPO has been found to be important for megakaryocyte proliferation and/or differentiation (Ishibashi et al., 1987; Broudy et al., 1995) (Papayannopoulou et al., 1996). Recent studies have also provided evidence for nonhematopoietic effects of EPO. For instance, EPOR expression was detected in umbilical cord and placental endothelial cells (Anagnostou et al., 1990, 1994) and neurons (Liu et al., 1994; Digicaylioglu et al., 1995; Morishita et al., 1996; Liu et al. 1997). EPO has been shown to promote endothelial cell proliferation in vitro (Anagnostou et al., 1990, 1994), and to assist neuron recovery from injury (Digicaylioglu et al., 1995). We and others have investigated the physiological role of EPO and EPOR on erythropoiesis and animal development by generating mice lacking EPO (Wu et al., 1995) or EPOR (Wu et al., 1995; Lin et al., 1996; Kieran et al., 1996). We showed that EPO and EPOR play a vital role in controlling processes such as proliferation, survival, and irreversible terminal differentiation of erythroid progenitors (Wu et al., 1995; Lin et al., 1996; Kieran et al., 1996). In this study, we demonstrated a novel function of EPO and EPOR in embryonic heart development. We showed that both EPO−/− and EPOR−/− mice suffer from ventricular hypoplasia which is coupled to defects in the intraventricular septum. The cardiac abnormalities are likely due to a reduction in cell proliferation. Reduction in cell division appears specific to the heart, since proliferation in other organs, including brain in EPOR null animals is indistinguishable from that in wild-type mice. Interestingly, no EPOR expression could be detected in myocardium. Instead, a high level of EPOR expression was detected in the endocardium, epicardium, and pericardium. By injecting marked EPOR−/− ES cells into wild-type blastocysts and analyzing ES cell contribution in the chimeric animals, we showed that EPOR−/− ES cells could contribute widely to the normal structure and development of cardiomyocytes, indicating that EPO triggers cardiomyocyte proliferation probably in a non-cell-autonomous manner. 3597 Development 126, 3597-3605 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 DEV4186