title: Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice.
abstract: Lgr4 and Lgr5 are known markers of adult and embryonic tissue stem cells in various organs. However, whether Lgr4 and Lgr5 are important for embryonic development remains unclear. To study their functions during intestinal crypt, skin and kidney development we now generated mice lacking either Lgr4 (Lgr4KO), Lgr5 (Lgr5KO) or both receptors (Lgr4/5dKO). E16.5 Lgr4KO mice displayed complete loss of Lgr5+/Olfm4+intestinal stem cells, compromised Wnt signaling and impaired proliferation and differentiation of gut epithelium. Similarly, E16.5 Lgr4KO mice showed reduced basal cell proliferation and hair follicle numbers in the developing skin, as well as dilated kidney tubules and ectatic Bowman׳s spaces. Although Lgr4KO and Lgr5KO mice both died perinatally, Lgr5 deletion did not compromise embryonic development of gut, kidney or skin. Concomitant deletion of Lgr4 and Lgr5 did not prevent perinatal lethality, in contrast to a previous report that suggested rescue of Lgr5 KO perinatal lethality by a hypomorphic Lgr4 mutant. While the double deletion did not further promote the phenotypes observed in Lgr4KO intestines, impaired kidney cell proliferation, reduced epidermal thickness, loss of Lgr5+follicular epithelium and impaired hair follicle development were only observed in Lgr4/5dKO mice. This supports complementary functions of both receptors. Our findings clearly establish the importance of Lgr4 and Lgr5 during embryonic gut, skin and kidney development, with a dominant role of Lgr4.
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Pikiolek
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Orsini
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Sprunger
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Isken
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Svenja
authors.initials: S
authors.lastname: Zietzling
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Desplanches
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Valerie
authors.initials: V
authors.lastname: Dubost
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Breustedt
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA, USA.
authors.forename: Reginald
authors.initials: R
authors.lastname: Valdez
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Diethilde
authors.initials: D
authors.lastname: Theil
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Dietrich
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: heinz.ruffner@novartis.com.
authors.forename: Heinz
authors.initials: H
authors.lastname: Ruffner
authors.affiliation: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: jan.tchorz@novartis.com.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Tchorz
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D017931:DNA Primers / Q000235:genetics; D040461:Gene Components; D005838:Genotype; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D007422:Intestines / Q000196:embryology*; D007668:Kidney / Q000196:embryology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000196:embryology*; D013234:Stem Cells / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; C496200:LGR4 protein, mouse; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: Intestine; Kidney; Mouse development; Skin; Tissue stem cell; Wnt signaling