Sci. STKE, 13 January 2004
DEVELOPMENT From Potential to Permanent
If your heart's in the right place, it is on the left side of your body, consistent with the asymmetric left-right distribution of most internal organs in vertebrates. The earliest common vertebrate feature of asymmetric gene expression is an increase in the left-sided expression of the growth factor Nodal around the node (a midline region that organizes establishment of the body plan). Nodal expression, which is self-sustaining, depends on activation of the Notch signaling pathway, but the mechanisms whereby early transient breaks in asymmetry lead to Notch activation remain poorly understood (see Monk). Raya et al. defined the expression patterns of components of the Notch pathway in chick embryos and developed a mathematical model that predicted that Nodal expression could arise from a transient increase in the effectiveness of Notch activation by its ligands. Pharmacologic analysis indicated that a known asymmetry in H+/K+-ATPase activity could be involved in asymmetric Nodal expression. The authors used two-photon excitation microscopy to show a transient asymmetric distribution of perinodal extracellular calcium concentration ([Ca2+]o) that depended on H+/K+-ATPase activity. Manipulation of [Ca2+]o with calcium-saturated agarose plugs or beads coated with a calcium chelator implicated this asymmetry in [Ca2+]o in asymmetric Notch activation and heart development. Moreover, ligand-dependent stimulation of Notch activity in a co-culture system was sensitive to physiological changes in [Ca2+]o, whereas ligand-independent activation of a Notch reporter was not. Thus, the transient asymmetry in perinodal [Ca2+]o that results from asymmetric H+/K+-ATPase activity and the consequent gradient in cell membrane potential could provide a localized mechanism for increasing the effectiveness with which Notch is activated by its ligands (as predicted by the model) and thereby produce a permanent change in the body plan.
Á. Raya, Y. Kawakami, C. Rodríguez-Esteban, M. Ibañes, D. Rasskin-Gutman, J. Rodríguez-Léon, D. Büscher, J. A. Feíjo, J. C. Izpisúa Belmonte, Notch activity acts as a sensor for extracellular calcium during vertebrate left-right determination. Nature 427, 121-128 (2004). [Online Journal]
N. Monk, Asymmetric fixation. Nature 427, 111-112 (2004). [Online Journal]
Citation: From Potential to Permanent. Sci. STKE 2004, tw18 (2004).
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