The enigma of the numb-Notch relationship during mammalian embryogenesis.
Asymmetric cell division is an attractive means to diversify cell fates during development and for stem cells to balance self-renewal and differentiation. In Drosophila, two signaling pathways, one mediated by Numb and the other by Notch, play essential but antagonistic roles in enabling the two daughters to adopt different fates after a wide variety of asymmetric cell divisions. However, recent studies show that mutating mammalian Numb homologues, m-Numb and Numblike (Numbl or Nbl), and eliminating Notch signaling in the developing nervous system both lead to premature depletion of neural stem/progenitor cells in mice. These findings raise an interesting question as to whether and how the antagonistic roles of Numb and Notch signaling are conserved in vertebrates. Here we provide evidence that loss of m-Numb and Numbl outside the embryonic nervous system also causes phenotypes similar to those exhibited by mice with defective Notch signaling. We further show that very little Numb protein is necessary for embryogenesis and that the presence of different m-Numb isoforms is unlikely to provide a molecular basis for differential regulation of Notch signaling in mammals, as these isoforms are functionally indistinguishable in cell fate specification. We discuss possible mechanisms by which the antagonistic roles of Numb and Notch are evolutionarily conserved to meet the needs of stem cell maintenance during mammalian neurogenesis.
Petersen
Petur H
PH
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA.
Tang
Haiyan
H
Zou
Kaiyong
K
Zhong
Weimin
W
D000818:Animals; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology / Q000196:embryology*; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005801:Genes, Homeobox / Q000502:physiology; D008322:Mammals / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics*; D019170:Somites / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism
D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D020033:Protein Isoforms; D051880:Receptors, Notch