Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.
Spontaneous and engineered mutations in the Notch ligand Jagged2 produced the Syndactylism phenotype (Jiang, R.L., Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G., Gridley, T., 1998. Defects in limb, craniofacial, and thymic Development in Jagged2 mutant mice. Genes Dev. 12, 1046-1057; Sidow, A., Bulotsky, M.S., Kerrebrock, A.W., Bronson, R.T., Daly, M.J., Reeve, M.P., Hawkins, T.L., Birren, B.W., Jaenisch, R., Lander, E.S., 1997. Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389, 722-725). Given that additional ligands may be expressed in the developing limb bud, it was possible that loss of Jagged2 disabled only part of Notch function in the limb. In addition, it is not clear from the expression pattern of Jagged2 in the apical ectodermal ridge (AER) whether the ectodermal or mesenchymal compartment of the limb bud receives the Jagged2 signal. To elucidate the requirement for the Notch pathway in limb development, we have analyzed single and compound Notch receptor mutants as well as gamma-secretase-deficient limbs. Floxed alleles were removed either from the developing limb bud ectoderm (using Msx2-Cre) or from the mesenchyme (using Prx1-Cre). Our results confirm that Jagged2 loss describes the contribution of the entire Notch pathway to the mouse limb development and revealed that both Notch1 and 2 are required in the ectoderm to receive the Jagged2 signal. Interestingly, our allelic series allowed us to determine that Notch receives this signal at an early stage in the developmental process and that memory of this event is retained by the mesenchyme, where Notch signaling appears to be dispensable. Thus, Notch signaling plays a non-autonomous role in digit septation.
Pan
Yonghua
Y
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, Box 8103, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Liu
Zhenyi
Z
Shen
Jie
J
Kopan
Raphael
R
D000818:Animals; D017209:Apoptosis; D004475:Ectoderm / Q000166:cytology / Q000502:physiology; D047108:Embryonic Development; D005121:Extremities / Q000196:embryology* / Q000254:growth & development; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D008648:Mesoderm; D051379:Mice; D015202:Protein Engineering; D051881:Receptor, Notch1 / Q000502:physiology*; D051883:Receptor, Notch2 / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction
C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D051880:Receptors, Notch