Developmental biology: Integrating signals
Researchers reveal what happens when the BMP and MAPK signaling pathways – which are integrated at the level of their intracellular transducer, SMAD1 – are uncoupled in vivo.
Biological processes require the integration of many signals — from within the cells, from other cells and tissues, and of course from the environment. Aubin and colleagues now show what happens when the BMP (bone morphogenetic protein) and MAPK (mitogen-activated protein kinase) signalling pathways — which are integrated at the level of their intracellular transducer, SMAD1 — are uncoupled in vivo.
SMAD1 has been extensively studied in vitro. Its phosphorylation at the C-terminus is required to relay the BMP signal into the nucleus, whereas phosphorylation of the SMAD1 linker region by the MAPK signal prevents its entry into the nucleus. Taking advantage of this knowledge to understand the fine-tuning of these pathways in vivo, Aubin et al. made two mutant mouse lines: a mutation in the SMAD1 C-terminus (SMAD1C) of one and in the SMAD1 linker region (SMAD1L) of the other abolished transduction of the BMP and MAPK signals, respectively.
The comparison of SMAD1C and SMAD1L mutant phenotypes with that of the SMAD1 null was revealing. SMAD1C mice died as embryos, like the null mice. Although the phenotypes were similar, some of them differed in severity from the SMAD1-/- mice. As the authors point out, the less severe phenotypes indicate that not all SMAD1 functions are to do with BMP signalling. The more severe phenotypes are more intriguing; they could reveal aspects of development that are especially sensitive to an equilibrium between BMP and MAPK signalling.
SMAD1L mutants survive into adulthood, but careful analysis of adult tissues revealed two important processes that require MAPK signalling — early germ-line formation and establishing the balance of cell types in the stomach epithelium. Because early germ-line formation is rescued in SMAD1C/SMAD1L mutants, SMAD1C and SMAD1L complement each other, which indicates that normal germ-cell development requires a balance of BMP and MAPK signals.
Aubin and colleagues provide convincing evidence that a balance between BMP and MAPK is crucial for development and tissue maintenance in vivo. As is often the case, their results raise more questions than they answer. One thing is clear — by creating these mutant strains, the authors have created an excellent tool that will be used in the context of further insights into signal integration in vivo.
Magdalena Skipper
References
- Aubin, J. et al. In vivo convergence of BMP and MAPK signalling pathways: impact of differential Smad1 phosphorylation on development and homeostasis. Genes Dev. 18, 1482–1494 (2004) | Article | PubMed |
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