Ruffner, Heinz, Pikiolek, Monika, Sprunger, Joelle, Isken, Andrea, Dubost, Valerie, Valdez, Reginald, Liu, Dong, Theil, Diethilde, Mueller, Matthias, Dietrich, Bill, Bouwmeester, Antonius, Kinzel, Bernd and Tchorz, Jan (2015) Combined deletion of Lgr4 and Lgr5 impairs embryonic mouse development. Dev Biol.

Abstract

Lgr4 and Lgr5 proteins are known markers of adult and embryonic tissue stem cells in various organs. However, the role of these proteins in propagating and maintaining individual tissue stem cell compartments is still controversial. While it was reported that Lgr4 is dispensable for normal embryonic gut development, Lgr4 deletion functionally impaired maintenance of the postnatal and adult intestinal crypt stem cell compartment. Furthermore, concomitant deletion of Lgr4 in Lgr5-null embryos was able to rescue their perinatal lethality, whereas combined deletion of Lgr4 and Lgr5 in adult mice exacerbated the latter phenotype, suggesting antagonistic or complementary functions of both receptors, respectively. While the effects of Lgr4 deletion during embryonic skin and kidney development have been reported, combined deletion of Lgr4 and Lgr5 has not been studied to date. To elucidate the functions of Lgr4 and Lgr5 during intestinal crypt development and to study their role in developing kidney and skin, we generated homozygous mice lacking either Lgr4 (Lgr4KO), Lgr5 (Lgr5KO) or both receptors (Lgr4/5dKO). Lgr4 deletion resulted in loss of Lgr5+ intestinal stem cells and impaired proliferation in the developing gut of E16.5 mice, a phenotype that was not further increased nor ameliorated by combined deletion of Lgr4 and Lgr5 (Lgr4/5dKO). In skin, E16.5 Lgr4KO and Lgr4/5dKO mice displayed impaired proliferation of basal cell progenitors accompanied by reduced epidermal thickness and reduced numbers of hair follicles. In contrast to E16.5 Lgr4KO mice, Lgr4/5dkO mice did neither show dilated kidney tubules nor cysts. However, E16.5 Lgr4/5dKO mice showed impaired kidney cell proliferation which was not observed in Lgr4KO mice. In summary, our data show that combined deletion of Lgr4 and Lgr5 impairs embryonic development with a dominant role of Lgr4 and support a complementary rather than an antagonistic function for both receptors.

Item Type:	Article
Date Deposited:	28 Apr 2016 23:45
Last Modified:	28 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/10657