Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination.
During vertebrate embryo development, the breaking of the initial bilateral symmetry is translated into asymmetric gene expression around the node and/or in the lateral plate mesoderm. The earliest conserved feature of this asymmetric gene expression cascade is the left-sided expression of Nodal, which depends on the activity of the Notch signalling pathway. Here we present a mathematical model describing the dynamics of the Notch signalling pathway during chick embryo gastrulation, which reveals a complex and highly robust genetic network that locally activates Notch on the left side of Hensen's node. We identify the source of the asymmetric activation of Notch as a transient accumulation of extracellular calcium, which in turn depends on left-right differences in H+/K+-ATPase activity. Our results uncover a mechanism by which the Notch signalling pathway translates asymmetry in epigenetic factors into asymmetric gene expression around the node.
Raya
Angel
A
Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Kawakami
Yasuhiko
Y
Rodríguez-Esteban
Concepción
C
Ibañes
Marta
M
Rasskin-Gutman
Diego
D
Rodríguez-León
Joaquín
J
Büscher
Dirk
D
Feijó
José A
JA
Izpisúa Belmonte
Juan Carlos
JC
D000818:Animals; D030161:Avian Proteins; D019521:Body Patterning / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005775:Gastrula / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D016695:Glycosyltransferases / Q000235:genetics / Q000378:metabolism; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D055457:Nodal Protein; D009853:Omeprazole / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D030161:Avian Proteins; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; C526007:NODAL protein, human; C497761:NOTCH1 protein, human; D055457:Nodal Protein; D011506:Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C064045:delta protein; D004533:Egtazic Acid; D016695:Glycosyltransferases; C498394:LFNG protein, Gallus gallus; C498393:LFNG protein, human; D017506:H(+)-K(+)-Exchanging ATPase; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D009853:Omeprazole