title: NDR Kinases Are Essential for Somitogenesis and Cardiac Looping during Mouse Embryonic Development.
abstract: Studies of mammalian tissue culture cells indicate that the conserved and distinct NDR isoforms, NDR1 and NDR2, play essential cell biological roles. However, mice lacking either Ndr1 or Ndr2 alone develop normally. Here, we studied the physiological consequences of inactivating both NDR1 and NDR2 in mice, showing that the lack of both Ndr1/Ndr2 (called Ndr1/2-double null mutants) causes embryonic lethality. In support of compensatory roles for NDR1 and NDR2, total protein and activating phosphorylation levels of the remaining NDR isoform were elevated in mice lacking either Ndr1 or Ndr2. Mice retaining one single wild-type Ndr allele were viable and fertile. Ndr1/2-double null embryos displayed multiple phenotypes causing a developmental delay from embryonic day E8.5 onwards. While NDR kinases are not required for notochord formation, the somites of Ndr1/2-double null embryos were smaller, irregularly shaped and unevenly spaced along the anterior-posterior axis. Genes implicated in somitogenesis were down-regulated and the normally symmetric expression of Lunatic fringe, a component of the Notch pathway, showed a left-right bias in the last forming somite in 50% of all Ndr1/2-double null embryos. In addition, Ndr1/2-double null embryos developed a heart defect that manifests itself as pericardial edemas, obstructed heart tubes and arrest of cardiac looping. The resulting cardiac insufficiency is the likely cause of the lethality of Ndr1/2-double null embryos around E10. Taken together, we show that NDR kinases compensate for each other in vivo in mouse embryos, explaining why mice deficient for either Ndr1 or Ndr2 are viable. Ndr1/2-double null embryos show defects in somitogenesis and cardiac looping, which reveals their essential functions and shows that the NDR kinases are critically required during the early phase of organogenesis.
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Debora
authors: D
authors: Schmitz-Rohmer
authors: Department of Biomedicine, Developmental Genetics, University of Basel, Basel, Switzerland.
authors: Simone
authors: S
authors: Probst
authors: Model Animal Research Center of Nanjing University, Pukou District, NanJing, P.R. China.
authors: Zhong-Zhou
authors: ZZ
authors: Yang
authors: Department of Biomedicine, Developmental Genetics, University of Basel, Basel, Switzerland.
authors: Frédéric
authors: F
authors: Laurent
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Swiss Institute of Bioinformatics, Maulbeerstrasse 66, Basel, Switzerland.
authors: Michael B
authors: MB
authors: Stadler
authors: Department of Biomedicine, Developmental Genetics, University of Basel, Basel, Switzerland.
authors: Aimée
authors: A
authors: Zuniga
authors: Department of Biomedicine, Developmental Genetics, University of Basel, Basel, Switzerland.
authors: Rolf
authors: R
authors: Zeller
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Debby
authors: D
authors: Hynx
authors: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors: Brian A
authors: BA
authors: Hemmings
authors: UCL Cancer Institute, University College London, London, United Kingdom.
authors: Alexander
authors: A
authors: Hergovich
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D047108:Embryonic Development / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D038081:Organogenesis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485172:Ndr2 protein, mouse; D011506:Proteins; C552947:NDR1 protein kinase, mouse; D017346:Protein Serine-Threonine Kinases