1. Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
2. Instituto Gulbenkian de Ciencia, Rua Da Quinta Grande n6, 2780-901 Oeiras, Portugal
3. Centro de Biotecnologia Vegetal, Faculdade de Ciencias, Universidade Lisboa, 1749-016 Lisboa, Portugal
4. These authors contributed equally to this work

Correspondence to: Juan Carlos Izpisúa Belmonte¹ Email: belmonte@salk.edu

Abstract

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.

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