Nuclear exclusion of Smad2 is a mechanism leading to loss of competence.
Controlling the duration of a signalling process in development by loss of competence is important because too strong an induction can change cell fate. To understand some of the mechanisms that underlie loss of competence, we have analysed the transduction of transforming growth factor-beta (TGF-beta) signalling during mesoderm formation, which is thought to be induced by TGF-beta-like signalling, in embryos of the frog Xenopus laevis. Here we show that gastrula ectoderm has the ability to express mesodermal marker genes in response to the TGF-beta signalling molecule activin for many hours, but then loses this ability within 1 h for all mesodermal genes tested. This loss of mesodermal competence correlates with the inability of Smad2, the principal intracellular signal transducer of activin, to accumulate in the nucleus. Mutating three phosphorylation sites within Smad2 abrogates the temporal restriction of Smad2 to accumulate in the nucleus. Overexpression of this mutant form of Smad2 can prolong the competence of endogenous mesodermal genes to respond to activin signalling. Thus, restricting the subcellular localization of an intracellular signal transducer constitutes a mechanism that leads to loss of mesodermal competence. This mechanism operates within less than an hour, and is therefore well suited to control an orderly sequence of inductions.
Grimm
Oliver H
OH
Wellcome Trust/Cancer Research UK Institute, Tennis Court Road, University of Cambridge, Cambridge, CB2 1QR, UK.
Gurdon
J B
JB
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D015415:Biomarkers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D029867:Xenopus Proteins; D014982:Xenopus laevis
D015415:Biomarkers; D004268:DNA-Binding Proteins; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins